Hemiasterlin derivatives and uses thereof

ABSTRACT

The present invention provides compounds having formula (I): 
     
       
         
         
             
             
         
       
         
         
           
             and additionally provides methods for the synthesis thereof and methods for the use thereof in the treatment of cancer, wherein R 1 –R 7 , X 1 , X 2 , R, Q, and n are as defined herein.

PRIORITY CLAIM

The present application claims the benefit under 35 U.S.C. § 371 ofInternational Application No.: PCT/US03/08888 (published PCT applicationNo. WO 03/82268), filed Mar. 21, 2003, which claims priority to U.S.Provisional Patent Application No. 60/366,592, filed Mar. 22, 2002, eachof the above cited applications is incorporated herein by reference inits entirety.

BACKGROUND OF THE INVENTION

Hemiasterlin (1) was first isolated from the sponge Hemiasterella minor(class, Demospongiae; order, Hadromedidia; family, Hemiasterllidae)collected in Sodwana Bay, South Africa (see Kaslunan et al. U.S. Pat.No. 5,661,175). It was reported that Hemiasterlin exhibited antitumoractivity against several cell lines, including human lung carcinoma,human colon carcinoma and human melanoma.

After the initial isolation and reporting of this compound, additionalhemiasterlins were isolated, and several hemiasterlin derivatives weresynthesized and their biological activity was also investigated. It wassubsequently reported that Hemiasterlin and certain analogs thereofexhibit antimitotic activity and thus are useful for the treatment ofcertain cancers (see, U.S. Pat. No. 6,153,590 and PCT application WO99/32509). However, only a rather limited number of Hemiasterlin analogswere prepared, half of which were the natural products themselves,isolated from Cymbastela sp., or were obtained by modifications to thenatural products. Thus the number and types of derivatives that could beprepared and evaluated for biological activity were limited.

Clearly, there remains a need to develop synthetic methodologies toaccess and examine the therapeutic effect of a variety of novelderivatives of Hemiasterlin, particularly those that are inaccessible bymaking modifications to the natural product. It would also be ofparticular interest to develop novel compounds that exhibit a favorabletherapeutic profile in vivo (e.g., are safe and effective, whileretaining stability in biological media).

SUMMARY OF THE INVENTION

As discussed above, there remains a need to develop novel Hemiasterlinanalogs to evaluate their potential as therapeutic agents for thetreatment of cancer. The present invention provides novel compounds ofgeneral formula (I),

and additionally provides methods for the synthesis thereof and methodsfor the use thereof in the treatment of cancer, wherein R₁–R₇, X₁, X₂,R, Q, and n are as defined herein. The inventive compounds also find usein the prevention of restenosis of blood vessels subject to traumas suchas angioplasty and stenting.

DETAILED DESCRIPTION OF CERTAIN PREFERRED EMBODIMENTS OF THE INVENTION

In recognition of the need to access and further explore the biologicalactivity of novel derivatives of Hemiasterlin, and this class ofpeptides in general, the present invention provides novel peptidecompounds, as described in more detail herein, which demonstrateantitumor activity. Thus, the compounds of the invention, andpharmaceutical compositions thereof, are useful for the treatment ofcancer. In certain embodiments, the compounds of the present inventioncan be used for the treatment of diseases and disorders including, butnot limited to prostate, breast, colon, bladder, cervical, skin,testicular, kidney, ovarian, stomach, brain, liver, pancreatic oresophageal cancer, lymphoma, leukemia and multiple myeloma. In certainother embodiments, the inventive compounds also find use in theprevention of restenosis of blood vessels subject to traumas such asangioplasty and stenting.

1) General Description of Compounds of the Invention

The compounds of the invention include compounds of the general formula(I) as further defined below:

wherein n is 0, 1, 2, 3 or 4;

-   X₁ and X₂ are each independently CR_(A)R_(B), C(═O), or —SO₂—;    wherein each occurrence of R_(A) and R_(B) is independently    hydrogen, or an aliphatic, alicyclic, heteroaliphatic,    heteroalicyclic, aryl or heteroaryl moiety;-   R₁ and R₂ are each independently hydrogen, —(C═O)R_(C) or an    aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or    heteroaryl moiety; wherein each occurrence of R_(C) is independently    hydrogen, OH, OR_(D), or an aliphatic, alicyclic, heteroaliphatic,    heteroalicyclic, aryl or heteroaryl moiety; wherein RD is an    aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or    heteroaryl moiety;-   each occurrence of R₃ and R₄ is independently hydrogen, or an    aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or    heteroaryl moiety; or wherein any two R₁, R₂, R₃ and R₄ groups,    taken together, may form an alicyclic, heteroalicyclic,    alicyclicc(aryl), heteroalicyclic(aryl), alicyclic(heteroaryl) or    heteroalicyclic(heteroaryl) moiety, or an aryl or heteroaryl moiety;-   R₅, R₆ and R₇ are each independently hydrogen, —(C═O)R_(E) or an    aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or    heteroaryl moiety, wherein each occurrence of R_(E) is independently    hydrogen, OH, OR_(F), or an aliphatic, alicyclic, heteroaliphatic,    heteroalicyclic, aryl or heteroaryl moiety, or wherein any two R₅,    R₆ and R₇ groups, taken together, form an alicyclic,    heteroalicyclic, alicyclic(aryl), heteroalicyclic(aryl),    alicyclic(heteroaryl) or heteroalicyclic(heteroaryl) moiety, or an    aryl or heteroaryl moiety; wherein R_(F) is an aliphatic, alicyclic,    heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; or R₇    may be absent when NR₇ is linked to R via a double bond;-   R is an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl    or heteroaryl moiety; and-   Q is OR^(Q′), SR^(Q′), NR^(Q′)R^(Q″), N₃, ═N—OH, or an aliphatic,    alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl    moiety; wherein R^(Q′) and R^(Q″) are each independently hydrogen,    or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl    or heteroaryl moiety, or R^(Q′) and R^(Q″), taken together with the    nitrogen atom to which they are attached, may form an alicyclic,    heteroalicyclic, alicyclic(aryl), heteroalicyclic(aryl),    alicyclic(heteroaryl) or heteroalicyclic(heteroaryl) moiety, or an    aryl or heteroaryl moiety; and    pharmaceutically acceptable derivatives thereof.

In certain embodiments, compounds of formula (I) and compounds describedin classes and subclasses herein, are not naturally occurringHemiasterlins.

In certain embodiments, compounds of formula (I) and compounds describedin classes and subclasses herein, do not have the following structure:

In certain embodiments of compounds described directly above andcompounds as described in certain classes and subclasses herein, thecompounds do not comprise more than four consecutive α-amino acidresidues, and/or one or more of the following groups do not occursimultaneously as defined:

-   (a) n is 1;    -   X₁ and X₂ are each C(═O);    -   R₁ and R₂ are each independently hydrogen, aliphatic, alicyclic,        heteroaliphatic, heteroalicyclic, Ar-aliphatic-, Ar-alicyclic-;        and, where at least one of R₁ and R₂ is aliphatic, alicyclic,        heteroaliphatic, heteroalicyclic, Ar-aliphatic-, Ar-alicyclic-        and neither are Ar, Ar-aliphatic- or Ar-alicyclic-, R₁ and R₂,        taken together, may form a three- to seven-membered ring;        wherein Ar is defined as substituted or unsubstituted phenyl,        naphtyl, anthracyl, phenanthryl, furyl, pyrrolyl, thiophenyl,        benzofuryl, benzothiophenyl, quinolyl, isoquinolyl, imidazolyl,        thiazolyl, oxazolyl or pyridyl;    -   R₃ is hydrogen;    -   R₄ is —CR_(4a)R_(4b)R_(4c), wherein R_(4a) and R_(4b) are each        independently hydrogen, aliphatic, alicyclic, heteroaliphatic,        heteroalicyclic, Ar-aliphatic-, Ar-alicyclic-; and, where at        least one of R_(4a) and R_(4b) is aliphatic, alicyclic,        heteroaliphatic, heteroalicyclic, Ar-aliphatic-, Ar-alicyclic-        and neither are Ar, Ar-aliphatic- or Ar-alicyclic-, R_(4a) and        R_(4b), taken together, may form a three- to seven-membered        ring; and R_(4c), is hydrogen, aliphatic, alicyclic,        heteroaliphatic, heteroalicyclic, Ar-aliphatic-, Ar-alicyclic-        and Ar; wherein Ar is as defined directly above;    -   R₅, R₆ and R₇ are each independently hydrogen, aliphatic,        alicyclic, heteroaliphatic, heteroalicyclic, Ar-aliphatic-,        Ar-alicyclic- and Ar;    -   R is a moiety selected from the group consisting of: a linear,        saturated or unsaturated, substituted or unsubstituted alkyl        group containing one to six carbon atoms; and    -   Q is —OR_(G), —SR_(G), —NR_(G)R_(H), —NHCH(R_(K))CO₂H, or        —NRCH(R_(K))CO₂H, wherein R_(G) and R_(H) are each independently        hydrogen, aliphatic, alicyclic, heteroaliphatic or        heteroalicyclic; R_(K) is aliphatic, alicyclic, heteroaliphatic,        heteroalicyclic, or a moiety having the structure        —(CH₂)_(t)NR_(K1)R_(K2), wherein t=1–4 and R_(K1) and R_(K2) are        independently hydrogen, aliphatic, alicyclic, heteroaliphatic,        heteroalicyclic or —C(NH)(NH₂);-   (b) n is 1;    -   X₁ and X₂ are each C(═O);    -   R₁ is an optionally substituted methylene or —CH═ group bonded        to the indole moiety thereby forming a tricyclic moiety;    -   R₂ is hydrogen, an optionally substituted alkyl or acyl group,        or is absent when R₁ is —CH═ as defined above;    -   R₃ is hydrogen or is absent when CR₃ and CR_(y)R_(z), as defined        herein, are linked by a double bond;    -   R₄ is a moiety having the structure:

-   -   wherein R_(w), R_(y) and R_(z) are each independently hydrogen,        or optionally substituted alkyl or acyl, or R_(z) is absent when        CR₃ and CR_(y)R_(z), as defined herein, are linked by a double        bond; R_(x) is hydrogen or an optional substituent, or is absent        when R₁ is an optionally substituted methylene or —CH═ group as        defined above; Y is an optional substituent; and m is 0, 1, 2, 3        or 4;    -   R₅ is hydrogen, OH or an optionally substituted alkyl or acyl        group;    -   R₆ is hydrogen or an optionally substituted alkyl group;    -   R₇ is hydrogen or alkyl; and    -   —R—X₂-Q together represent an optionally substituted alkyl        moiety;

-   (c) n is 1;    -   X₁ and X₂ are each C(═O);    -   R₁ is hydrogen, an optionally substituted alkyl or acyl group,        or an optionally substituted methylene or —CH═ group bonded to        the indole moiety thereby forming a tricyclic moiety;    -   R₂ is hydrogen, an optionally substituted alkyl or acyl group,        or is absent when R₁ is —CH═ as defined above;    -   R₃ is hydrogen or is absent when CR₃ and CR_(y)R_(z), as defined        herein, are linked by a double bond;    -   R₄ is a moiety having the structure:    -   wherein R_(w), R_(y) and

R_(z) are each independently hydrogen, or optionally substituted alkylor acyl, or R_(z) is absent when CR₃ and CR_(y)R_(z), as defined herein,are linked by a double bond; with the limitation that R_(y) and R_(z)are not simultaneously hydrogen; R_(x) is hydrogen or an optionalsubstituent, or is absent when R₁ is an optionally substituted methyleneor —CH═ group as defined above; Y is an optional substituent; and m is0, 1, 2, 3 or 4;

-   -   R₅ is hydrogen, OH or an optionally substituted alkyl or acyl        group;    -   R₆ is hydrogen or an optionally substituted alkyl group;    -   R₇ is hydrogen or alkyl; and    -   —R—X₂-Q together represent an optionally substituted alkyl        moiety or -Q′-C(O)X, wherein Q′ is an optionally substituted        —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH═CH—, —CH₂C═C— or phenylene        moiety, wherein X is —OR′, —SR′ or —NR′R″ and each occurrence of        R′ and R″ is independently hydrogen or optionally substituted        alkyl;

-   (d) n is 1;    -   X₁ is C═O;    -   R₁ is methyl;    -   R₂ and R₃, taken together, form a piperidine moiety;    -   R₄ and R₅ are each hydrogen,    -   R₆ is —CH(CH₃)CH₂CH₃;    -   R₇ is —CH₂OC(═O)CH₂CH(CH₃)₂, —CH₂OC(═O)CH₂CH₂CH₃ or        —CH₂OC(═O)CH₂CH₃; and    -   —R—X₂-Q together represent the moiety having the structure:

-   (e) n is 1;    -   X₁ is C═O;    -   R₁, R₂, and R₇ are each methyl;    -   R₃ and R₅ are each hydrogen;    -   R₄ and R₆ are each i-propyl; and    -   —R—X₂-Q together represent the moiety having the structure:

-   -    wherein R_(x) is hydrogen or 2-thiazolyl; and/or

-   (f) n is 1;    -   X₁ is C═O;    -   R₁ and R₂ are each independently hydrogen or C₁₋₄alkyl;    -   R₃ and R₅ are each hydrogen;    -   R₄ and R₆ are each i-propyl;    -   R₇ is methyl; and    -   —R—X₂-Q together represent a moiety having the structure:

-   -   wherein v is 0, 1 or 2;    -   R′ is hydrogen or C₁₋₄alkyl;    -   R″ is C₁₋₆alkylamino; hydroxy; C₃₋₇cycloalkylamino optionally        substituted by phenyl or benzyl; arylamino; C₁₋₄alkoxy;        benzhydrazino; heterocyclyl optionally substituted with one to        three substituents selected from the group consisting of benzyl,        benzhydryl, alkyl, hydroxy, alkoxy, alkylcarbamoyloxy, amino,        mono- or di-alkylamino, acylamino, alkoxycarbonylamino, phenyl        or halogen; heterocyclylamino; heterocycloalkylamino with the        heterocyclyc group optionally substituted with one to three        substituents selected from the group consisting of benzyl,        benzhydryl, alkyl, hydroxy, alkoxy, alkylcarbamoyloxy, amino,        di-alkylamino, acylamino, alkoxycarbonylamino or halogen;        aralkyloxy or aralkyl both optionally substituted with one to        three substituents selected from the group consisting of        halogen, alkoxyxarbonyl, sulfamoyl, alkylcarbonyloxy, cyano,        mono- or di-alkylamino, alkyl, alkoxy, phenyl, phenoxy,        trifluoromethyl, trifluoromethoxy, alkylthio, hydroxy,        alkoxycarbonylamino, heterocyclyl, 1,3-dioxolyl, 1,4-dioxolyl,        amino, aminosulfonyl or benzyl; or aralkylamino having        C₁₋₄alkylene and the aryl group optionally substituted with one        to three substituents selected from the group consisting of        halogen, alkoxyxarbonyl, sulfamoyl, alkylcarbonyloxy,        carbamoyloxy, cyano, mono- or di-alkylamino, alkyl, alkoxy,        phenyl, phenoxy, trifluoromethyl, trifluoromethoxy, alkylthio,        hydroxy, alkoxycarbonylamino, heterocyclyl, 1,3-dioxolyl,        1,4-dioxolyl, amino or benzyl; and    -   R′″ is hydrogen, alkyl optionally substituted with one to three        substituents selected from the group consisting of hydroxy,        alkoxy, amino, mono- or di-alkylamino, carboxy, alkoxycarbonyl,        carbamoyl, alkylcarbonyloxy, carbamoyloxy or halogen; alkenyl;        alkynyl; C₃₋₇cycloalkyl; aryl optionally substituted with one to        three substituents selected from the group consisting of        halogen, alkoxyxarbonyl, sulfamoyl, alkylcarbonyloxy, cyano,        mono- or di-alkylamino, alkyl, alkoxy, phenyl, phenoxy,        trifluoromethyl, trifluoromethoxy, alkylthio, hydroxy,        alkoxycarbonylamino, heterocyclyl, 1,3-dioxolyl, 1,4-dioxolyl,        amino or benzyl; aralkyl with the aryl group optionally        substituted with one to three substituents selected from the        group consisting of halogen, alkoxyxarbonyl, carbamoyl,        sulfamoyl, alkylcarbonyloxy, cyano, mono- or di-alkylamino,        alkyl, alkoxy, phenyl, phenoxy, trifluoromethyl,        trifluoromethoxy, alkylthio, hydroxy, alkoxycarbonylamino,        heterocyclyl, 1,3-dioxolyl, 1,4-dioxolyl, amino or benzyl; or        heterocyclylalkyl;    -   wherein the groups recited in paragraph (f) above are defined as        follows:    -   alkyl refers to a straight-chain or branched-chain hydrocarbon        group optionally substituted with hydroxy, alkoxy, amino, mono-        or di-alkylamino, acetoxy, alkylcarbonyloxy, alkoxycarbonyl,        carbamoyloxy, carbamoyl or halogen;    -   alkenyl refers to a hydrocarbon chain as defined for alkyl above        having at least one double bond;    -   alkynyl refers to a hydrocarbon chain as defined for alkyl above        having at least one triple bond;    -   C₃₋₇cycloalkyl refers to a saturated, cyclic hydrocarbon group        with 3–7 carbon atoms optionally substituted with alkyl, phenyl,        amino, hydroxy or halogen;    -   C₁₋₄alkylene refers to a biradical linear or branched        hydrocarbon chain containing 1–4 carbon atoms;    -   Aralkyl, refers to an aryl group attached to an alkylene group;    -   Heterocyclyl refers to saturated, unsaturated or aromatic        monovalent cyclic radical having one to three heteroatoms        selected from O, N and S, or combination thereof, optionally        substituted with one or more occurrences of benzyl, benzhydryl,        alkyl, hydroxy, alkoxy, alkylcarbamoyloxy, amino, mono- or        di-alkylamino, acylamino, alkoxycarbonyl amino or halogen;    -   Amino refers to —NH₂ and includes amino groups which are further        substituted by lower alkyl groups, or nitrogen protecting groups        know in the art;    -   Cycloalkylamino refers to cycloalkyl groups as defined above        attached to a structure via an amino radical;    -   Arylamino is defined as aryl-NH—;    -   Aralkylamino is defined as aralkyl-NH—;    -   Carbamoyl refers to the group —C(═O)—NH₂;    -   Carbamoyloxy refers to the group —O—C(═O)—NH—;    -   Alkylcarbamoyloxy refers to the group —O—C(═O)—NH-alkyl;    -   Alkylcarbonyloxy refers to the group —O—C(═O)-alkyl;    -   Aralkyloxy refers to the group —O-aralkyl; and    -   Alkylthio refers to the group Alkyl-S—.

In certain other embodiments of compounds described in (a) above andcompounds as described in certain classes and subclasses herein, thefollowing groups do not occur simultaneously as defined:

-   n is 1; X₁ and X₂ are each C(═O); R₁ and R₂ are each independently    hydrogen, methyl, ethyl, propyl, n-butyl, acetyl; or R₁ and R₂,    taken together, form a moiety selected from the group consisting of    cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; R₃ is    hydrogen; R₄ is —CR_(4a)R_(4b)R_(4c) wherein R_(4a) and R_(4b) are    each independently methyl, ethyl, n-propyl or n-butyl; or β_(4a) and    R_(4b), taken together, form a moiety selected from the group    consisting of β-cyclopropyl, β-cyclobutyl, β-cyclopentyl, and    β-cyclcohexyl; and R_(4c) is phenyl, naphtyl, anthracyl or pyrrolyl;    R₅ and R₇ are each independently hydrogen or methyl; R₆ is a three    to six carbon, branched alkyl group; and —R—X₂-Q together represent    the moiety having the structure:

-   -   wherein R′ is methyl, ethyl, n-propyl, isopropyl, tert-butyl,        iso-butyl, or sec-butyl; R″ is hydrogen, methyl, ethyl, propyl,        iso-propyl, n-butyl, iso-butyl or sec-butyl; and Q is OH or        OR_(G) wherein R_(G) is a linear or branched one to six carbon        alkyl group.

In certain other embodiments of compounds described in (a) above andcompounds as described in certain classes and subclasses herein, thefollowing groups do not occur simultaneously as defined:

-   n is 1; X₁ and X₂ are each C(═O); R₁, R₃ and R₅ are each hydrogen;    R₂ is methyl; R₄ is —CR_(4a)R_(4b)R_(4c), R is tert-butyl; and    —R—X₂-Q together represent the moiety having the structure:

-   wherein R′ is isopropyl; R″ is methyl; and Q is OH; and    -   (a) R_(4a) and R_(4b) are each methyl; R_(4c) is methyl or        phenyl; and R₇ is hydrogen or methyl;    -   (b) R_(4a) and R_(4b) are each methyl; R_(4c) is hydrogen; and        R₇ is methyl; or    -   (c) R_(4a) and R_(4b) are each hydrogen; R_(4c) is phenyl; and        R₇ is methyl.

In certain other embodiments, compounds of formula (I) and compoundsdescribed in classes and subclasses herein, do not have the structure ofany one or more of the compounds disclosed on page 8 line 28 throughpage 25 line 9, page 28 line 1 through page 32 line 9 and page 39 line16 through page 80 line 20 of WO 03/008378, which is incorporated hereinby reference in its entirety.

In certain other embodiments, compounds of formula (I) and compoundsdescribed in classes and subclasses herein, do not have the structure ofany one or more of the compounds disclosed on page 10 line 24 throughpage 17 line 18, page 17 line 26 through page 19 line 3, page 19 line 10through page 20 line 3, page 20 line 17 through page 21 line 9, page 21lines 14–29, page 22 lines 1–12, page 22 lines 16–18, page 22 lines22–27, page 23 line 1 through page 24 line 21, page 24 line 26 throughpage 25 line 9, and page 28 line 1 through page 32 line 9 of WO03/008378.

In certain other embodiments, compounds of formula (a) and compoundsdescribed in classes and subclasses herein, do not have the structure ofany one or more of the compounds disclosed in Nieman J. et al.,“Synthesis and Antitumotic/Cytotoxic Activity of HemiasterlinAnalogues”, Journal of Natural Products, 2003, 66(2):183–199, which isincorporated herein by reference in its entirety.

In certain embodiments, compounds of formula (I) and compounds describedin classes and subclasses herein, do not have any one or more of thefollowing structure:

In certain other embodiments, compounds of formula (I) are defined asfollows:

-   X₁ and X₂ are each independently CHR_(A)R_(B), SO₂ or C═O; wherein    R_(A) and R_(B) are each independently hydrogen or substituted or    unsubstituted, linear or branched, cyclic or acyclic, or saturated    or unsaturated lower alkyl;-   R₁ and R₂ are each independently hydrogen, or a linear or branched,    cyclic or acyclic, or saturated or unsaturated lower alkyl, lower    heteroalkyl or acyl moiety, or an aryl or heteroaryl moiety; wherein    the alkyl, heteroalkyl, and aryl moieties may be substituted or    unsubstituted; or-   R₁ and R₂, taken together, may form a saturated or unsaturated,    substituted or unsubstituted cyclic ring of 5 to 8 atoms;-   each occurrence of R₃ and R₄ is independently hydrogen, or a linear    or branched, cyclic or acyclic, or saturated or unsaturated lower    alkyl, lower heteroalkyl, lower-alkyl(aryl), lower-heteroalkyl(aryl)    moiety, or an aryl or heteroaryl moiety; wherein the alkyl,    heteroalkyl, -alkyl(aryl), heteroalkyl(aryl), aryl and heteroaryl    moieties may be substituted or unsubstituted; or-   R₃ and R₄, taken together, may form a saturated or unsaturated,    substituted or unsubstituted cyclic ring of 3 to 8 atoms;-   the carbon atom bearing R₃ and R₄ may be of S configuration;-   n is 1;-   R₅ is hydrogen or a protecting group; wherein the protecting group    may be a nitrogen protecting group;-   R₆ is hydrogen or substituted or unsubstituted, linear or branched,    cyclic or acyclic, or saturated or unsaturated lower alkyl or    heteroalkyl; or a substituted or unsubstituted aryl or heteroaryl    moiety;-   the carbon atom bearing R₆ may be of S configuration;-   R₇ is hydrogen, or substituted or unsubstituted, linear or branched,    cyclic or acyclic, or saturated or unsaturated lower alkyl or    heteroalkyl; or a substituted or unsubstituted aryl or heteroaryl    moiety; or R₇ may be absent when NR₇ is linked to R via a double    bond;-   R is a substituted or unsubstituted, linear or branched, cyclic or    acyclic, or saturated or unsaturated alkyl moiety; or a    heteroaliphatic moiety containing 1–10 carbon atoms, 1 to 4 nitrogen    atoms, 0 to 4 oxygen atoms and 0 to 4 sulfur atoms; whereby the    heteroaliphatic moiety may be substituted or unsubstituted, linear    or branched, cyclic or acyclic, or saturated or unsaturated;-   wherein (i) the alkyl moiety may have the structure:

-   wherein R_(8a), R_(9a) and R_(10a) are each independently absent,    hydrogen, or substituted or unsubstituted, linear or branched,    cyclic or acyclic, or saturated or unsaturated lower alkyl or    heteroalkyl; or a substituted or unsubstituted aryl or heteroaryl    moiety; wherein any two R₇, R_(8a), R_(9a) and R_(10a) groups may    form a substituted or unsubstituted, saturated or unsaturated cyclic    alkyl, heteroalkyl, alky(aryl) or heteroalkyl(aryl) moiety, or an    aryl or heteroaryl moiety; and wherein the carbon atom bearing    R_(8a) may be of S configuration;-   (ii) the heteroalkyl moiety may have the structure:

-   -   wherein R_(8b), R_(9b), R_(10b) and R_(11b) are each        independently absent, hydrogen, or substituted or unsubstituted,        linear or branched, cyclic or acyclic, or saturated or        unsaturated lower alkyl, heteroalkyl or acyl; or a substituted        or unsubstituted aryl or heteroaryl moiety; wherein any two R₇,        R_(8b), R_(9b), R_(10b) and R_(11b) groups may form a        substituted or unsubstituted, saturated or unsaturated cyclic        alkyl, heteroalkyl, alky(aryl) or heteroalkyl(aryl) moiety, or a        substituted or unsubstituted aryl or heteroaryl moiety; wherein        NR₇ and CR_(8b), CR_(8b) and CR_(9b), CR_(9b) and NR_(10b), and        NR_(10b) and CR_(11b) are each independently linked by a single        or double bond as valency permits; and wherein the carbon atom        bearing R_(8b) may be of S configuration;

-   (iii) or the heteroalkyl moiety may have the structure:

-   -   wherein R_(8c), R_(9c), R_(10c), R_(11c) and R_(12c) are each        independently absent, hydrogen, or substituted or unsubstituted,        linear or branched, cyclic or acyclic, or saturated or        unsaturated lower alkyl or heteroalkyl; or a substituted or        unsubstituted aryl or heteroaryl moiety; wherein any two R₇,        R_(8c), R_(9c), R_(10c), R_(11c) and R_(12c) groups may form a        substituted or unsubstituted, saturated or unsaturated cyclic        alkyl, heteroalkyl, ally(aryl) or heteroalkyl(aryl) moiety, or a        substituted or unsubstituted aryl or heteroaryl moiety; wherein        NR₇ and CR_(8c), CR_(8c) and CR_(9c), CR_(9c) and CR_(10c),        CR_(10c) and CR_(11c) are each independently linked by a single        or double bond as valency permits; and wherein the carbon atom        bearing R_(8c) may be of S configuration; and

-   Q is OR^(Q′), SR^(Q′), NR^(Q′)R^(Q″), wherein R^(Q′) and R^(Q″) are    each independently hydrogen or a substituted or unsubstituted,    linear or branched, cyclic or acyclic, or saturated or unsaturated    lower alkyl or heteroalkyl moiety, or a substituted or unsubstituted    aryl or heteroaryl moiety; or wherein R^(Q′) and R^(Q″), taken    together, may form a substituted or unsubstituted, saturated or    unsaturated cyclic alkyl or heteroalkyl moiety or a substituted or    unsubstituted aryl or heteroaryl moiety; and    pharmaceutically acceptable derivatives thereof.

In certain embodiments, the present invention defines certain classes ofcompounds which are of special interest. For example, one class ofcompounds of special interest includes those compounds having thestructure of formula (I) in which R is —CH(R_(8a))C(R_(8a))═C(R_(10a))—and the compound has the structure (Ia):

-   wherein R₁–R₇, X₁, X₂, Q and n are defined in classes and subclasses    herein;-   R_(8a), R_(9a) and R_(10a) are each independently hydrogen, or an    aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or    heteroaryl moiety; and wherein any two R₇, R_(8a), R_(9a) and    R_(10a) groups may form a substituted or unsubstituted, saturated or    unsaturated alicyclic, heteroalicyclic, alicyclic(aryl),    heteroalicyclic(aryl), alicyclic(heteroaryl) or    heteroalicyclic(heteroaryl) moiety, or an aryl or heteroaryl moiety.

Another class of compounds of special interest, herein referred to asclass (Ib), consists of compounds having the structure of formula (I) inwhich X₂ is C═O and R is a heteroaliphatic moiety containing 1–10 carbonatoms, 1 to 4 nitrogen atoms, 0 to 4 oxygen atoms and 0 to 4 sulfuratoms, whereby the heteroaliphatic moiety may be substituted orunsubstituted, linear or branched, cyclic or acyclic, or saturated orunsaturated.

Another class of compounds of special interest consists of compoundshaving the structure of formula (I) in which X₁ is C═O; n is 1; R₁ andR₄, taken together, form a cyclic heterocyclic or heteroaryl moiety; R₃is hydrogen or is absent when the carbon atom bearing R₃ is linked to Nor E via a double bond; and the compound has the structure (Ic):

-   wherein R₂, R₅-R₇, R, X₂ and Q are defined in classes and subclasses    herein;-   each occurrence of G, J, L and M is independently CHR^(iv),    CR^(iv)R^(v), O, S, NR^(iv)R^(v), wherein each occurrence of R^(iv)    and R^(v) is independently absent, hydrogen, —C(═O)R^(vi), or an    aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or    heteroaryl moiety; or wherein any two adjacent R₂, R^(iv), R^(v) or    R^(vi) groups, taken together, form a substituted or unsubstituted,    saturated or unsaturated alicyclic or heteroalicyclic moiety    containing 3–6 atoms or an aryl or heteroaryl moiety; wherein each    occurrence of R^(vi) is an aliphatic, alicyclic, heteroaliphatic,    heteroalicyclic, aryl or heteroaryl moiety;-   N and G, G and J, J and L, L and M, M and CR₃, and CR₃ and N are    each independently linked by a single or double bond as valency    permits; and-   g, j, l and m are each independently 0, 1, 2, 3, 4, 5 or 6, wherein    the sum of g, j, l and m is 3–6.

Another class of compounds of special interest consists of compoundshaving the structure of formula (I) in which X₁ is C═O; n is 1; R₃ andR₄ are each independently an aliphatic, alicyclic, heteroaliphatic,heteroalicyclic, aryl or heteroaryl moiety, or, when taken together,form an alicyclic, heteroalicyclic, alicyclic(aryl),heteroalicyclic(aryl), alicyclic(heteroaryl) orheteroalicyclic(heteroaryl) moiety; and the compound has the structure(Id):

-   wherein R₁, R₂, R₅–R₇, R. X₂ and Q are defined in classes and    subclasses herein.

The following structures illustrate several exemplary types of compoundsof class (Ia). Additional compounds are described in the Exemplificationherein.

The following structures illustrate several exemplary types of compoundsof class (Ib). Additional compounds are described in the Exemplificationherein.

The following structures illustrate several exemplary types of compoundsof class (Ic). Additional compounds are described in the Exemplificationherein.

The following structures illustrate several exemplary types of compoundsof class (Id). Additional compounds are described in the Exemplificationherein.

Other compounds of the invention will be readily apparent to the reader.

A number of important subclasses of each of the foregoing classesdeserve separate mention; for example, one important subclass of class(Ia) includes those compounds having the structure of formula (Ia) inwhich X₂ is C═O; and the compound has the following structure:

wherein R₁–R₇, n and Q are defined in classes and subclasses herein;

-   R_(8a), R_(9a) and R_(10a) are each independently hydrogen, or an    alkyl, heteroalkyl, aryl or heteroaryl moiety; and wherein any two    R₇, R_(8a), R_(9a) and R_(10a) groups may form a cyclic alkyl,    heteroalkyl, -alkyl(aryl), -heteroalykl(aryl), -alkyl(heteroaryl) or    -heteroalkyl(heteroaryl) moiety, or an aryl or heteroaryl moiety;    and-   X₁ is CR_(A)R_(B), SO₂ or C═O; wherein R_(A) and R_(B) are each    independently hydrogen, alkyl, heteroalkyl, aryl or heteroaryl.

Another important subclass of class (Ia) includes those compounds havingthe structure of formula (Ia) in which X₁ is C═O; and the compound hasthe following structure:

-   wherein R₁–R₇, n and Q are defined in classes and subclasses herein;-   R_(8a), R_(9a) and R_(10a) are each independently hydrogen, or an    alkyl, heteroalkyl, aryl or heteroaryl moiety; and wherein any two    R₇, R_(8a), R_(9a) and R_(10a) groups may form a cyclic alkyl,    heteroalkyl, -alkyl(aryl), -heteroalykl(aryl), -alkyl(heteroaryl) or    -heteroalkyl(heteroaryl) moiety, or an aryl or heteroaryl moiety;    and-   X₂ is CR_(A)R_(B), SO₂ or C═O; wherein R_(A) and R_(B) are each    independently hydrogen, alkyl, heteroalkyl, aryl or heteroaryl.-   Another important subclass of class (Ia) includes those compounds    having the structure of formula (Ia) in which X₁ and X₂ are each    C═O; n is 1; R₃ is hydrogen; R₄ is a moiety having the structure    —CR_(4a)R_(4b)R_(4c); and the compound has the following structure:

-   wherein R₁–R₂, R₅-R₇ and Q are defined in classes and subclasses    herein; and-   R_(4a) and R_(4b) are each independently hydrogen or lower alkyl or    heteroalkyl, and R_(4c) is aryl or heteroaryl; and-   R_(8a), R_(9a) and R_(10a) are each independently hydrogen, or an    alkyl, heteroalkyl, aryl or heteroaryl moiety; and wherein any two    R₇, R_(8a), R_(9a) and R_(10a) groups may form a cyclic alkyl,    heteroalkyl, -alkyl(aryl), -heteroalykl(aryl), -alkyl(heteroaryl) or    -heteroalkyl(heteroaryl) moiety, or an aryl or heteroaryl moiety.

Another important subclass of class (Ia) includes those compounds havingthe structure of formula (Ia) in which X₁ and X₂ are each C═O; Q is anoptionally substituted nitrogen-containing cyclic moiety; and thecompound has the following structure:

-   wherein R₁–R₇ and n are defined in classes and subclasses herein;-   R_(8a), R_(9a) and R_(10a) are each independently hydrogen, or an    alkyl, heteroalkyl, aryl or heteroaryl moiety; and wherein any two    R₇, R_(8a), R_(9a) and R_(10a) groups may form a cyclic alkyl,    heteroalkyl, -alkyl(aryl), -heteroalykl(aryl), -alkyl(heteroaryl) or    -heteroalkyl(heteroaryl) moiety, or an aryl or heteroaryl moiety;-   each occurrence of A, B, D or E is independently CHR^(i),    CR^(i)R^(ii), O, S, N wherein each occurrence of R^(i) and R^(ii) is    independently absent, hydrogen, —C(═O)R^(iii), or an aliphatic,    alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl    moiety; or wherein any two adjacent R^(i), R^(ii) or R^(iii) groups,    taken together, form a alicyclic or heteroalicyclic moiety    containing 3–6 atoms or an aryl or heteroaryl moiety; wherein each    occurrence of R^(iii) is an aliphatic, alicyclic, heteroaliphatic,    heteroalicyclic, aryl or heteroaryl moiety;-   N and A, A and B, B and D, D and E, and E and N are each    independently linked by a single or double bond as valency permits;    and-   a, b, d and e are each independently 0, 1, 2, 3, 4, 5, 6 or 7,    wherein the sum of a, b, d and e is 4–7.

Another important subclass of class (Ia) includes those compounds havingthe structure of formula (Ia) in which X₁ and X₂ are each C═O; Q is anoptionally substituted nitrogen-containing cyclic moiety; n is 1; R₃ ishydrogen; R₄ is a moiety having the structure —CR_(4a)R_(4b)R_(4c); andthe compound has the following structure:

-   wherein R₁, R₂, R₅–R₇, A, B, D, E, a, b, d and e are defined in    classes and subclasses herein;-   R_(4a) and R_(4b) are each independently hydrogen or lower alkyl or    heteroalkyl, and R_(4c) is a substituted or unsubstituted aryl or    heteroaryl group;-   R_(8a), R_(9a) and R_(10a) are each independently hydrogen, or an    alkyl, heteroalkyl, aryl or heteroaryl moiety; and wherein any two    R₇, R_(8a), R_(9a) and R_(10a) groups may form a cyclic alkyl,    heteroalkyl, -alkyl(aryl), -heteroalykl(aryl), -alkyl(heteroaryl) or    -heteroalkyl(heteroaryl) moiety, or an aryl or heteroaryl moiety.

A number of important subclasses of each of the foregoing subclasses ofclass (Ia) deserve separate mention; these subclasses include subclassesof the foregoing subclasses of class (Ia) in which:

-   i-a. R₁ and R₂ are independently hydrogen or substituted or    unsubstituted, linear or branched, cyclic or acyclic, saturated or    unsaturated lower alkyl, heteroalkyl, -alkyl(aryl) or acyl;-   ii-a. R₁ is hydrogen and R₂ is substituted or unsubstituted, linear    or branched, cyclic or acyclic, saturated or unsaturated lower    alkyl, heteroalkyl, -alkyl(aryl) or acyl;-   iii-a. R₁ is hydrogen and R₂ is substituted or unsubstituted, linear    or branched, cyclic or acyclic, saturated or unsaturated lower    alkyl;-   iv-a. R₁ is hydrogen and R₂ is methyl, ethyl, propyl, butyl, pentyl,    tert-butyl, i-propyl, —CH(CH₃)CH₂CH₃, —CH(CH₃)CH₂CH₂CH₃,    —CH₂CH(CH₃)₂, —CH(CH₃)CH(CH₃)₂, —CH(CH₃)₂CH₂CH₃, —CH(CH₃)cyclobutyl,    —CH(Et)₂, —CH(CH₃)₂C CH, cyclohexyl, cyclopentyl, cyclobutyl or    cyclopropyl;-   v-a. R₁ and R₂ are each hydrogen;-   vi-a. The carbon atom bearing R₃ and R₄ is of S configuration;-   vii-a. R₃ is hydrogen and R₄ is substituted or unsubstituted, linear    or branched, cyclic or acyclic, or saturated or unsaturated lower    alkyl, heteroalkyl or -alkyl(aryl) or substituted or unsubstituted    aryl or heteroaryl;-   viii-a R₃ is hydrogen and R₄ is —CR_(4a)R_(4b)R_(4c); wherein R_(4a)    and R_(4b) are independently hydrogen, or a substituted or    unsusbtituted, linear or branched, cyclic or acyclic, saturated or    unsaturated lower alkyl moiety and R_(4c) is substituted or    unsubstituted aryl or heteroaryl;-   ix-a. R₃ is hydrogen and R₄ is —CR_(4a)R_(4b)Ph; wherein R_(4a) and    R_(4b) are independently hydrogen, or a substituted or    unsusbtituted, linear or branched, cyclic or acyclic, saturated or    unsaturated lower alkyl moiety;-   x-a. R₄ is a substituted or unsubstituted 3-indole moiety;-   xi-a. R₃ is hydrogen;-   xii-a. R₁ and R₄, taken together, form a substituted or    unsubstituted pyrrolidine group;-   xiii-a. R₁ and R₄, taken together, form a substituted or    unsubstituted piperidine group;-   xiv-a. R₁ and R₄, taken together, form a substituted or    unsubstituted thiazolidine group;-   xv-a. R₁ and R₄, taken together, form a substituted or unsubstituted    morpholine group;-   xvi-a. R₁ and R₄, taken together, form a substituted or    unsubstituted thiomorpholine group;-   xvii-a. R₁ and R₄, taken together, form a substituted or    unsubstituted indole group;-   xviii-a. R₃ and R₄ are each independently substituted or    unsubstituted, linear or branched, cyclic or acyclic, or saturated    or unsaturated lower alkyl, heteroalkyl or -allyl(aryl) or    substituted or unsubstituted aryl or heteroaryl;-   xix-a. R₃ and R₄ are each independently substituted or    unsubstituted, linear or branched, cyclic or acyclic or saturated or    unsaturated lower alkyl, -alkyl(aryl) or substituted or    unsubstituted aryl;-   xx-a. R₃ and R₄ are each independently substituted or unsubstituted    lower alkyl, aryl or heteroaryl;-   xxi-a. R₃ and R₄ are each independently methyl, ethyl, propyl,    butyl, pentyl, tert-butyl, i-propyl, —CH(CH₃)CH₂CH₃,    —CH(CH₃)CH₂CH₂CH₃, —CH₂CH(CH₃)₂, —CH(CH₃)CH(CH₃)₂, —CH(CH₃)₂CH₂CH₃,    —CH(CH₃)cyclobutyl, —CH(Et)₂, cyclohexyl, cyclopentyl, cyclobutyl,    cyclopropyl, phenyl, —C₁₋₆alkylOR^(a), —C₁₋₆alkylSR^(a) or    —CR^(a)R^(b)R^(c); wherein R^(a) and R^(b) are independently    hydrogen, substituted or unsubstituted, linear or branched, cyclic    or acyclic, or saturated or unsaturated lower alkyl and R^(c) is    substituted or unsubstituted aryl or heteroaryl;-   xxii-a. R₃ and R₄ are each independently methyl, ethyl, propyl,    butyl, pentyl, tert-butyl, i-propyl, —CH(CH₃)CH₂CH₃,    —CH(CH₃)CH₂CH₂CH₃, —CH₂CH(CH₃)₂, —CH(CH₃)CH(CH₃)₂, —CH(CH₃)₂CH₂CH₃,    —CH(CH₃)cyclobutyl, —CH(Et)₂, cyclohexyl, cyclopentyl, cyclobutyl,    cyclopropyl, phenyl, —C₁₋₆alkylOR^(a), —C₁₋₆alkylSR^(a) or    —CR^(b)R^(c)Ph; wherein R^(a) is hydrogen, substituted or    unsubstituted, linear or branched, cyclic or acyclic, or saturated    or unsaturated lower alkyl and R^(b) And R^(c) are each    independently substituted or unsubstituted linear or branched,    cyclic or acyclic, or saturated or unsaturated lower alkyl;-   xxiii-a. R₃ and R₄ are each ethyl;-   xxiv-a. R₃ is phenyl and R₄ is lower alkyl;-   xxv-a. R₃ is phenyl and R₄ is ethyl;-   xxvi-a. R₃ and R₄, taken together, form a substituted or    unsubstituted cycloalkyl group;-   xxvii-a. R₃ and R₄, taken together, form a cyclohexyl group;-   xxviii-a. R₃ and R₄, taken together, form a substituted or    unsubstituted cycloalkyl(aryl) group;-   xxix-a. R₅ is hydrogen;-   xxx-a. R₆ is substituted or unsubstituted, linear or branched,    cyclic or acyclic, saturated or unsaturated lower alkyl;-   xxxi-a. R₆ is methyl, ethyl, propyl, butyl, pentyl, tert-t-butyl,    i-propyl, —CH(CH₃)CH₂CH₃, —CH₂CH(CH₃)₂, cyclohexyl, cyclopentyl,    cyclobutyl or cyclopropyl;-   xxxii-a. R₆ is tert-butyl;-   xxxiii-a. The R₆-bearing carbon atom is of S configuration;-   xxxiv-a. R₇ is substituted or unsubstituted, linear or branched,    cyclic or acyclic, saturated or unsaturated lower alkyl;-   xxxv-a. R₇ is methyl;-   xxxvi-a. R is —CH(R_(8a))C(R_(9a))═C(R_(10a))—; and    -   a) R_(8a) is substituted or unsubstituted, linear or branched,        cyclic or acyclic, saturated or unsaturated lower alkyl;    -   b) R_(8a) is iso-propyl;    -   c) The R_(8a)-bearing carbon atom is of S configuration;    -   d) R_(9a) is hydrogen or substituted or unsubstituted, linear or        branched, cyclic or acyclic, saturated or unsaturated lower        alkyl;    -   e) R_(9a) is hydrogen;    -   f) R_(10a) is hydrogen or substituted or unsubstituted, linear        or branched, cyclic or acyclic, saturated or unsaturated lower        alkyl;    -   g) R_(10a) is methyl;-   xxxvii-a. n is 1;-   xxxviii-a. X₁ is C═O;-   xxxix-a. X₁ is CH₂;-   xl-a. X₁ is SO₂;-   xli-a. X₂ is C═O;-   xlii-a. X₂ is CH₂;-   xliii-a. X₂ is SO₂;-   xliv-a. Q is OR^(Q′), SR^(Q′), NR^(Q′)R^(″), N₃, ═N—OH, or a moiety    selected from the group consisting of:

-   wherein each occurrence of r is 0, 1 or 2; s and t are independently    an integer from 0–8; X is O, S, or NR^(K); each occurrence of R^(Q1)    and R^(Q2) is independently hydrogen, halogen, —CN, —S(O)_(h)R^(J),    —NO₂, —COR^(J), —CO₂R^(J), —NR^(J)COR^(J), —NR^(J)CO₂R^(J),    —CON^(J)R^(J), —CO(NOR^(J))R^(J), aliphatic, alicyclic,    heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, or    -Z_(t)R^(J); wherein h is 1 or 2; and Z, is independently —O—, —S—,    NR^(K), —C(O)—, wherein each occurrence of R^(J) and R^(K) is    independently hydrogen, COR^(L), COOR^(L), CONR^(L)R^(M),    —NR^(L)R^(M), —S(O)₂R^(L), or an aliphatic, alicyclic,    heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, and    wherein each occurrence of R^(L) and R^(M) is independently    hydrogen, or an aliphatic, alicyclic, heteroaliphatic,    heteroalicyclic, aryl or heteroaryl moiety; and R^(Q′) and R^(Q″)    are independently hydrogen, or a substituted or unsubstituted,    linear or branched, cyclic or acyclic alkyl or heteroalkyl moiety,    or a substituted or unsubstituted aryl or heteroaryl moiety; or    R^(Q′) and R^(Q″), taken together with the nitrogen atom to which    they are attached, form a substituted or unsubstituted heterocyclic,    aryl or heteroaryl moiety; and-   xlv-a. Q is OR^(Q′), SR^(Q′), NR^(Q′)R^(Q″), N₃, ═N—OH, or a moiety    selected from the group consisting of:

-   -   wherein each occurrence of r is 0, 1 or 2; s and t are        independently an integer from 0–8; each occurrence of R^(Q1) and        R^(Q2) is independently hydrogen, or a substituted or        unsubstituted, linear or branched, cyclic or acyclic alkyl or        heteroalkyl moiety, or a substituted or unsubstituted aryl or        heteroaryl moiety; or R^(Q1) and R^(Q2), taken together with the        nitrogen atom to which they are attached, form a substituted or        unsubstituted heterocyclic moiety; and R^(Q′) and R^(Q″) are        independently hydrogen, or a substituted or unsubstituted,        linear or branched, cyclic or acyclic alkyl or heteroalkyl        moiety, or a substituted or unsubstituted aryl or heteroaryl        moiety; or R^(Q′) and R^(Q″), taken together with the nitrogen        atom to which they are attached, form a substituted or        unsubstituted heterocyclic, aryl or heteroaryl moiety; and/or

-   xliv-a. Q is OR^(Q′), SR^(Q′), NR^(Q′)R^(Q″), N₃, ═N—OH, or a moiety    selected from the group consisting of:

-   -   wherein each occurrence of r is 0, 1 or 2; and R^(Q′) and R^(Q″)        are independently hydrogen, or a substituted or unsubstituted,        linear or branched, cyclic or acyclic alkyl or heteroalkyl        moiety, or a substituted or unsubstituted aryl or heteroaryl        moiety; or R^(Q′) and R^(Q″), taken together with the nitrogen        atom to which they are attached, form a substituted or        unsubstituted heterocyclic, aryl or heteroaryl moiety.

An important subclass of class (Ib) includes those compounds having thestructure of formula (Ib) in which R is—C(R_(8b))C(R_(9b))N(R_(10b))C(R_(11b))—; and the compound has thefollowing structure:

-   wherein R₁–R₇, n, X₁ and Q are defined in classes and subclasses    herein;-   R_(8b), R_(9b), R_(10b) and R_(11b) are each independently absent,    hydrogen, —(C═O)R_(L) or an aliphatic, alicyclic, heteroaliphatic,    heteroalicyclic, aryl or heteroaryl moiety, wherein each occurrence    of R_(L) is independently hydrogen, OH, OR_(M), or an aliphatic,    alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl    moiety, or wherein any two R_(8b), R_(9b), R_(10b) and R_(11b)    groups, taken together, form a alicyclic or heteroalicyclic moiety,    or an aryl or heteroaryl moiety; wherein R_(M) is an aliphatic,    alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl    moiety; and-   NR₇ and CR_(8b), CR_(8b) and CR_(9b), CR_(9b) and NR_(10b), NR_(10b)    and CR_(11b) are each independently linked by a single or double    bond as valency permits.

Another important subclass of class (Ib) includes those compounds havingthe structure of formula (Ib) in which X₁ is C═O; R is—C(R_(8b))C(R_(9b))N(R_(10b))C(R_(11b))—; n is 1; R₃ is hydrogen; R₄ isa moiety having the structure —CR_(4a)R_(4b)R_(4c); and the compound hasthe following structure:

-   wherein R₁–R₂, R₅–R₇ and Q are defined in classes and subclasses    herein; and-   R_(4a) and R_(4b) are each independently hydrogen or lower alkyl and    R_(4c) is aryl or heteroaryl;-   R_(8b), R_(9b), R_(10b) and R_(11b) are each independently absent,    hydrogen, —(C═O)R_(L) or an aliphatic, alicyclic, heteroaliphatic,    heteroalicyclic, aryl or heteroaryl moiety, wherein each occurrence    of R_(L) is independently hydrogen, OH, OR_(M), or an aliphatic,    alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl    moiety, or wherein any two R_(8b), R_(9b), R_(10b) and R_(11b)    groups, taken together, form a alicyclic or heteroalicyclic moiety,    or an aryl or heteroaryl moiety; wherein R_(M) is an aliphatic,    alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl    moiety; and-   NR₇ and CR_(8b), CR_(8b) and CR_(9b), CR_(9b) and NR_(10b), NR_(10b)    and CR_(11b) are each independently linked by a single or double    bond as valency permits.

Another important subclass of class (Ib) includes those compounds havingthe structure of formula (Ib) in which R is—C(R_(8b))C(R_(9b))N(R_(10b))C(R_(11b))—; R_(10b) and R_(11b), takentogether, form a substituted or unsubstituted cyclic heteroalkyl orheteroaryl moiety; and the compound has the following structure:

-   wherein R₁–R₇, n and Q are defined in classes and subclasses herein;-   p is 1, 2, 3 or 4;-   q is 0–12;-   each occurrence of S₁ is independently an aliphatic, alicyclic,    heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, or any    two adjacent S₁ moieties, taken together, may form an an alicyclic,    heteroalicyclic, aryl or heteroaryl moiety;-   R_(8b) and R_(9b) are each independently absent, hydrogen,    —(C═O)R_(L) or an aliphatic, alicyclic, heteroaliphatic,    heteroalicyclic, aryl or heteroaryl moiety, wherein each occurrence    of R_(L) is independently hydrogen, OH, OR_(M), or an aliphatic,    alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl    moiety, or wherein R_(8b) and R_(9b), taken together, form a    alicyclic or heteroalicyclic moiety, or an aryl or heteroaryl    moiety; wherein R_(M) is an aliphatic, alicyclic, heteroaliphatic,    heteroalicyclic, aryl or heteroaryl moiety; and-   NR₇ and CR₈, and CR_(8b) and CR_(9b) are each independently linked    by a single or double bond as valency permits.

Another important subclass of class (Ib) includes those compounds havingthe structure of formula (Ib) in which n is 1; R isC(R_(8b))C(R_(9b))N(R_(10b))C(R_(11b))—; R_(10b) and R_(11b), takentogether, form a substituted or unsubstituted cyclic heteroalkyl orheteroaryl moiety; R₄ is a moiety having the structure—CR_(4a)R_(4b)R_(4c); and the compound has the following structure:

-   wherein R₁–R₇, X₁ and Q are defined in classes and subclasses    herein;-   p is 1, 2, 3 or 4;-   is 0, 1, 2, 3, 4, 5 or 6;-   each occurrence of S₁ is independently an aliphatic, alicyclic,    heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, or any    two adjacent S₁ moieties, taken together, may form an an alicyclic,    heteroalicyclic, aryl or heteroaryl moiety;-   R_(4a) and R_(4b) are each independently hydrogen or lower alkyl or    heteroalkyl; and R_(4c) is aryl or heteroaryl;-   R_(8b) and R_(9b) are each independently hydrogen, —(C═O)R_(L) or an    aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or    heteroaryl moiety, wherein each occurrence of R_(L) is independently    hydrogen, OH, OR_(M), or an aliphatic, alicyclic, heteroaliphatic,    heteroalicyclic, aryl or heteroaryl moiety, or wherein R_(8b) and    R_(9b), taken together, form a alicyclic or heteroalicyclic moiety,    or an aryl or heteroaryl moiety; wherein R_(M) is an aliphatic,    alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl    moiety; and-   NR₇ and CR_(8b), and CR_(8b) and CR_(9b) are each independently    linked by a single or double bond as valency permits.

Another important subclass of class (Ib) includes those compounds havingthe structure of formula (Ib) in which R is—C(R_(8c))C(R_(9c))C(R_(10c))C(R_(11c))OC(R_(12c))—; and the compoundhas the following structure:

-   wherein R₁–R₇, n, X₁ and Q are defined in classes and subclasses    herein;-   R_(8c), R_(9c), R_(10c), R_(11c) and R_(12c) are each independently    absent, hydrogen, —(C═O)R_(L) or an aliphatic, alicyclic,    heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, wherein    each occurrence of R_(L) is independently hydrogen, OH, OR_(M), or    an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or    heteroaryl moiety, or wherein any two R_(8c), R_(9c), R_(10c),    R_(11c) and R_(12c) groups, taken together, form a alicyclic or    heteroalicyclic moiety, or an aryl or heteroaryl moiety; wherein    R_(M) is an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic,    aryl or heteroaryl moiety; and-   NR₇ and CR_(8c), CR_(8c) and CR_(9c), CR_(9c) and CR_(10c), and    CR10, and CR_(11c) are each independently linked by a single or    double bond as valency permits.

Another important subclass of class (Ib) includes those compounds havingthe structure of formula (Ib) in which X₁ is C═O; n is 1; R₃ ishydrogen; R₄ is a moiety having the structure —CR_(4a)R_(4b)R_(4c); R is—C(R_(8c))C(R_(9c))C(R_(10c))C(R_(11c))OC(R_(12c))—; and the compoundhas the following structure:

-   wherein R₁, R₂, R₅–R₇ and Q are defined in classes and subclasses    herein;-   R_(4a) and R_(4b) are each independently hydrogen, or lower alkyl or    heteroalkyl; and R_(4c) is aryl or heteroaryl;-   R_(8c), R_(9c), R_(10c), R_(11c) and R_(12c) are each independently    absent, hydrogen, (C═O)R_(L) or an aliphatic, alicyclic,    heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, wherein    each occurrence of R_(L) is independently hydrogen, OH, OR_(M), or    an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or    heteroaryl moiety, or wherein any two R_(8c), R_(9c), R_(10c),    R_(11c) and R_(12c) groups, taken together, form a alicyclic or    heteroalicyclic moiety, or an aryl or heteroaryl moiety; wherein    R_(M) is an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic,    aryl or heteroaryl moiety; and-   NR₇ and CR_(8c), CR_(8c) and CR_(9c), CR_(9c), and CR_(10c), and    CR_(10c) and CR_(11c) are each independently linked by a single or    double bond as valency permits.

A number of important subclasses of each of the foregoing subclasses ofclass (Ib) deserve separate mention; these subclasses include subclassesof the foregoing subclasses of class (Ib) in which:

-   i-b. R₁ and R₂ are independently hydrogen or substituted or    unsubstituted, linear or branched, cyclic or acyclic, or saturated    or unsaturated lower alkyl, heteroalkyl, -alkyl(aryl) or acyl;-   ii-b. R₁ is hydrogen and R₂ is substituted or unsusbtituted, linear    or branched, cyclic or acyclic, saturated or unsaturated lower    alkyl, heteroalkyl, -alkyl(aryl) or acyl;-   iii-b. R₁ is hydrogen and R₂ is substituted or unsusbtituted, linear    or branched, cyclic or acyclic, saturated or unsaturated lower    alkyl;-   iv-b. R₁ is hydrogen and R₂ is methyl, ethyl, propyl, butyl, pentyl,    tert-butyl, i-propyl, —CH(CH₃)CH₂CH₃, —CH(CH₃)CH₂CH₂CH₃,    —CH₂CH(CH₃)₂, —CH(CH₃)CH(CH₃)₂, —CH(CH₃)₂CH₂CH₃, —CH(CH₃)cyclobutyl,    —CH(Et)₂, —CH(CH₃)₂C CH, cyclohexyl, cyclopentyl, cyclobutyl or    cyclopropyl;-   v-b. R₁ and R₂ are each hydrogen;-   vi-b. The carbon atom bearing R₃ and R₄ is of S configuration;-   vii-b. R₃ is hydrogen and R₄ is substituted or unsubstituted, linear    or branched, cyclic or acyclic, or saturated or unsaturated lower    alkyl, heteroalkyl or -alkyl(aryl) or substituted or unsubstituted    aryl or heteroaryl;-   viii-b. R₃ is hydrogen and R₄ is —CR_(4a)R_(4b)R_(4c); wherein    R_(4a) and R_(4b) are independently hydrogen, or a substituted or    unsusbtituted, linear or branched, cyclic or acyclic, saturated or    unsaturated lower alkyl moiety and R_(4c) is substituted or    unsubstituted aryl or heteroaryl;-   ix-b. R₃ is hydrogen and R₄ is —CR_(4a)R_(4b)Ph; wherein R_(4a) and    R_(4b) are independently hydrogen, or a substituted or    unsusbtituted, linear or branched, cyclic or acyclic, saturated or    unsaturated lower alkyl moiety;-   x-b. R₄ is a substituted or unsubstituted 3-indole moiety;-   xi-b. R₃ is hydrogen;-   xii-b. R₁ and R₄, taken together, form a substituted or    unsubstituted pyrrolidine group;-   xii-b. R₁ and R₄, taken together, form a substituted or    unsubstituted piperidine group;-   xiv-b. R₁ and R₄, taken together, form a substituted or    unsubstituted thiazolidine group;-   xv-b. R₁ and R₄, taken together, form a substituted or unsubstituted    morpholine group;-   xvi-b. R₁ and R₄, taken together, form a substituted or    unsubstituted thiomorpholine group;-   xvii-b. R₁ and R₄, taken together, form a substituted or    unsubstituted indole group;-   xviii-b. R₃ and R₄ are each independently substituted or    unsubstituted, linear or branched, cyclic or acyclic, or saturated    or unsaturated lower alkyl, heteroalkyl or -alkyl(aryl) or    substituted or unsubstituted aryl or heteroaryl;-   xix-b. R₃ and R₄ are each independently substituted or    unsubstituted, linear or branched, cyclic or acyclic, or saturated    or unsaturated lower alkyl, -alkyl(aryl) or substituted or    unsubstituted aryl;-   xx-b. R₃ and R₄ are each independently substituted or unsubstituted    lower alkyl, aryl or heteroaryl;-   xxi-b. R₃ and R₄ are each independently methyl, ethyl, propyl,    butyl, pentyl, tert-butyl, i-propyl, —CH(CH₃)CH₂CH₃,    —CH(CH₃)CH₂CH₂CH₃, —CH₂CH(CH₃)₂, —CH(CH₃)CH(CH₃)₂, —CH(CH₃)₂CH₂CH₃,    —CH(CH₃)cyclobutyl, —CH(Et)₂, cyclohexyl, cyclopentyl, cyclobutyl,    cyclopropyl, phenyl, —C₁₋₆alkylOR^(a), —C₁₋₆alkylSR_(a) or    —CR^(a)R^(b)R^(c);-   wherein R^(a) and R^(b) are independently hydrogen, substituted or    unsubstituted, linear or branched, cyclic or acyclic, or saturated    or unsaturated lower alkyl and R^(c) is substituted or unsubstituted    aryl or heteroaryl;-   xxii-b. R₃ and R₄ are each independently methyl, ethyl, propyl,    butyl, pentyl, tert-butyl, i-propyl, —CH(CH₃)CH₂CH₃,    —CH(CH₃)CH₂CH₂CH₃, —CH₂CH(CH₃)₂, —CH(CH₃)CH(CH₃)₂, —CH(CH₃)₂CH₂CH₃,    —CH(CH₃)cyclobutyl, —CH(Et)₂, cyclohexyl, cyclopentyl, cyclobutyl,    cyclopropyl, phenyl, —C alkylOR^(a), —C₁₋₆alkylSR^(a) or    —CR^(b)R^(c)Ph; wherein R^(a) is hydrogen, substituted or    unsubstituted, linear or branched, cyclic or acyclic, or saturated    or unsaturated lower alkyl and R^(b) And R^(c) are each    independently substituted or unsubstituted linear or branched,    cyclic or acyclic, or saturated or unsaturated lower alkyl;-   xxiii-b. R₃ and R₄ are each ethyl;-   xxiv-b. R₃ is phenyl and R₄ is lower alkyl;-   xxv-b. R₃ is phenyl and R₄ is ethyl;-   xxvi-b. R₃ and R₄, taken together, form a substituted or    unsubstituted cycloalkyl group;-   xxvii-b. R₃ and R₄, taken together, form a cyclohexyl group;-   xxviii-b. R₃ and R₄, taken together, form a substituted or    unsubstituted cycloalkyl(aryl) group;-   xxix-b. R₅ is hydrogen;-   xxx-b. R₆ is substituted or unsubstituted, linear or branched,    cyclic or acyclic, or saturated or unsaturated lower alkyl;-   xxxi-b. R₆ is methyl, ethyl, propyl, butyl, pentyl, tert-butyl,    i-propyl, —CH(CH₃)CH₂CH₃, —CH₂CH(CH₃)₂, cyclohexyl, cyclopentyl,    cyclobutyl or cyclopropyl;-   xxxii-b. R₆ is tert-butyl;-   xxxiii-b. The R₆-bearing carbon atom is of S configuration;-   xxxiv-b. R₇ is substituted or unsubstituted, linear or branched,    cyclic or acyclic, or saturated or unsaturated lower alkyl;-   xxxv-b. R₇ is methyl;-   xxxvi-b. R is —C(R_(8b))C(R_(9b))N(R_(10b))CR_(11b)— and    -   a) R_(8b) is substituted or unsubstituted, linear or branched,        cyclic or acyclic, or saturated or unsaturated lower alkyl;    -   b) R_(8b) is iso-propyl;    -   c) The R_(8b)-bearing carbon atom is of S configuration;    -   d) R_(9b) is hydrogen or substituted or unsubstituted, linear or        branched, cyclic or acyclic, or saturated or unsaturated lower        alkyl;    -   e) R_(10b) is hydrogen, substituted or unsubstituted, linear or        branched, cyclic or acyclic, or saturated or unsaturated lower        alkyl or acyl;    -   f) R_(10b) is hydrogen, methyl or acetyl;    -   g) R_(10b) and R_(11b), taken together, form a substituted or        unsubstituted pyrrolidine ring; or    -   h) R_(9b) and R_(11b), taken together, form a substituted or        unsubstituted thiazole ring;-   xxxvii-b. R is —C(R_(8c))C(R_(9c))C(R_(10c))CR_(11c)OR_(12c)— and    -   a) R_(8c) is substituted or unsubstituted, linear or branched,        cyclic or acyclic, or saturated or unsaturated lower alkyl;    -   b) R_(8c) is iso-propyl;    -   c) The R_(8c)-bearing carbon atom is of S configuration;    -   d) R_(9c) and R_(10c) are each independently hydrogen or        substituted or unsubstituted, linear or branched, cyclic or        acyclic, or saturated or unsaturated lower alkyl;    -   e) CR_(9c) and CR_(10c) are linked via a double bond;    -   f) CR_(9c) and CR_(10c) are linked via a double bond and R_(9c)        is hydrogen; or-   g) CR_(9c) and CR_(10c) are linked via a double bond and R_(10c) is    methyl;-   xxxviii-b. n is 1;-   xxxix-b. X₁ is C═O;-   xl-b. X₁ is CH₂;-   xli-b. X₁ is SO₂;-   xlii-b. Q is OR^(Q′), SR^(Q′), NR^(Q′)R^(Q″), N₃, ═N—OH, or a moiety    selected from the group consisting of:

-   -   wherein each occurrence of r is 0, 1 or 2; s and t are        independently an integer from 0–8; X is O, S, or NR^(K); each        occurrence of R^(Q1) and R^(Q2) is independently hydrogen,        halogen, —CN, —S(O)_(h)R^(J), —NO₂, —COR^(J), —CO₂R^(J),        —NR^(J)COR, —NR^(J)CO₂R^(J), —CONR^(J)R^(J), —CO(NOR^(J))R^(J),        aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or        heteroaryl moiety, or -Z₁R^(J); wherein h is 1 or 2; and Z₁ is        independently —O—, —S—, NR^(K), —C(O)—, wherein each occurrence        of R^(J) and R^(K) is independently hydrogen, COR^(L), COOR^(L),        CONR^(L)R^(M), —NR^(L)R^(M), —S(O)₂R^(L) or an aliphatic,        alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl        moiety, and wherein each occurrence of R^(L) and R^(M) is        independently hydrogen, or an aliphatic, alicyclic,        heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; and        R^(Q′) and R^(Q″) are independently hydrogen, or a substituted        or unsubstituted, linear or branched, cyclic or acyclic alkyl or        heteroalkyl moiety, or a substituted or unsubstituted aryl or        heteroaryl moiety; or R^(Q′) and R^(Q″), taken together with the        nitrogen atom to which they are attached, form a substituted or        unsubstituted heterocyclic, aryl or heteroaryl moiety;

-   xliii-b. Q is OR^(Q′), SR^(Q′), NR^(Q′)R^(Q″), N₃, ═N—OH, or a    moiety selected from the group consisting of:

-   -   wherein each occurrence of r is 0, 1 or 2; s and t are        independently an integer from 0–8; each occurrence of R^(Q1) and        R^(Q2) is independently hydrogen, or a substituted or        unsubstituted, linear or branched, cyclic or acyclic alkyl or        heteroalkyl moiety, or a substituted or unsubstituted aryl or        heteroaryl moiety; or R^(Q1) and R^(Q2), taken together with the        nitrogen atom to which they are attached, form a substituted or        unsubstituted heterocyclic moiety; and R^(Q′) and R^(Q″) are        independently hydrogen, or a substituted or unsubstituted,        linear or branched, cyclic or acyclic alkyl or heteroalkyl        moiety, or a substituted or unsubstituted aryl or heteroaryl        moiety; or R^(Q′) and R^(Q″), taken together with the nitrogen        atom to which they are attached, form a substituted or        unsubstituted heterocyclic, aryl or heteroaryl moiety; and/or

-   xliv-b. Q is OR^(Q′), SR^(Q′), NR^(Q′)R^(Q″), N₃, ═N—OH, or a moiety    selected from the group consisting of:

-   -   wherein each occurrence of r is 0, 1 or 2; and R^(Q′) and R^(Q″)        are independently hydrogen, or a substituted or unsubstituted,        linear or branched, cyclic or acyclic alkyl or heteroalkyl        moiety, or a substituted or unsubstituted aryl or heteroaryl        moiety; or R^(Q′) and R^(Q″), taken together with the nitrogen        atom to which they are attached, form a substituted or        unsubstituted heterocyclic, aryl or heteroaryl moiety.

An important subclass of class (Ic) includes those compounds having thestructure of formula (Ic) in which X₂ is C═O; R is—CH(R_(8a))C(R_(9a))═C(R_(10a))—; j is 0; l and m are each 1; R₃ ishydrogen; G is CR_(G1); M is CR_(M1)R_(M2), and the compound has thestructure:

-   wherein R₂, R₅–R₇ and Q are defined in classes and subclasses    herein;-   g is 1, 2, 3 or 4;-   R_(8a), R_(9a) and R_(10a) are each independently hydrogen, or an    alkyl, heteroalkyl, aryl or heteroaryl moiety; and wherein any two    R₇, R_(8a), R_(9a) and R_(10a) groups may form a cyclic alkyl,    heteroalkyl, -alkyl(aryl), -heteroalykl(aryl), -alkyl(heteroaryl) or    -heteroalkyl(heteroaryl) moiety, or an aryl or heteroaryl moiety;-   L is CR_(L1)R_(L2), S, O or NR_(L3), wherein each occurrence of    R_(L1), R_(L2) and R_(L3) is independently hydrogen or an aliphatic,    alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl    moiety;-   each occurrence of R_(G1), R_(M1) and R_(M2) is each independently    hydrogen or an aliphatic, alicyclic, heteroaliphatic,    heteroalicyclic, aryl or heteroaryl moiety;-   wherein any two adjacent R_(L1), R_(L2), R_(L3), R_(G1), R_(M1) or    R_(M2) groups, taken together, form a substituted or unsubstituted    alicyclic or heteroalicyclic moiety containing 3–6 atoms or an aryl    or heteroaryl moiety.

Another important subclass of class (Ic) includes those compounds havingthe structure of formula (Ic) in which X₂ is C═O; G, J and M are eachCH₂; j, l and m are each 1; R is —CH(R_(8a))C(R_(9a))═C(R_(10a))—; R₃ ishydrogen; and the compound has the structure:

-   wherein R₂, R₅-R₇ and Q are defined in classes and subclasses    herein;-   g is 0, 1, 2 or 3;-   R_(8a), R_(9a) and R_(10a) are each independently hydrogen, or an    alkyl, heteroalkyl, aryl or heteroaryl moiety; and wherein any two    R₇, R_(8a), R_(9a) and R_(10a) groups may form a cyclic alkyl,    heteroalkyl, -alkyl(aryl), -heteroalykl(aryl), -alkyl(heteroaryl) or    -heteroalkyl(heteroaryl) moiety, or an aryl or heteroaryl moiety;-   R_(L1) and R_(L2) are independently hydrogen or an aliphatic,    alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl    moiety.

Another important subclass of class (Ic) includes those compounds havingthe structure of formula (Ic) in which X₂ is C═O; R is—C(R_(8b))C(R_(9b))N(R_(10b))C(R_(11b))—; j is 0; 1 and m are each 1; R₃is hydrogen; G is CHR_(G1), M is CR_(M1)R_(M2), and the compound has thestructure:

-   wherein R₂, R₅–R₇ and Q are defined in classes and subclasses    herein;-   g is 1, 2 or 3;-   L is CR_(L1)R_(L2), S, O or NR_(L3), wherein each occurrence of    R_(L1), R_(L2) and R_(L3) is independently hydrogen or an aliphatic,    alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl    moiety;-   each occurrence of R_(G1), R_(M1) and R_(M2) is independently    hydrogen or an aliphatic, alicyclic, heteroaliphatic,    heteroalicyclic, aryl or heteroaryl moiety;-   any two adjacent R_(L1), R_(L2), R_(L3), R_(G1), R_(M1) or R_(M2)    groups, taken together, may form a substituted or unsubstituted    alicyclic or heteroalicyclic moiety containing 3–6 atoms or an aryl    or heteroaryl moiety;-   R_(8b), R_(9b), R_(10b) and R_(11b) are each independently absent,    hydrogen, —(C═O)R_(L) or an aliphatic, alicyclic, heteroaliphatic,    heteroalicyclic, aryl or heteroaryl moiety, wherein each occurrence    of R_(L) is independently hydrogen, OH, OR_(M), or an aliphatic,    alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl    moiety, or wherein any two adjacent R_(8b), R_(9b), R_(10b) and    R_(11b) groups, taken together, form a alicyclic or heteroalicyclic    moiety, or an aryl or heteroaryl moiety; wherein R_(M) is an    aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or    heteroaryl moiety; and-   NR₇ and CR_(8b), CR_(8b) and CR_(9b), CR_(9b) and NR_(10b), NR_(10b)    and CR_(11b) are each independently linked by a single or double    bond as valency permits.

Another important subclass of class (Ic) includes those compounds havingthe structure of formula (Ic) in which X₂ is C═O; R is(R_(8b))C(R_(9b))N(R_(10b))C(R_(11b))—; j is 0; l and m are each 1; R₃is hydrogen; G is CHR_(G1), M is CR_(M1)R_(M2); R_(10b) and R_(11b),taken together, form a cyclic heteroalkyl group; and the compound hasthe structure:

-   wherein R₂, R₅–R₇ and Q are defined in classes and subclasses    herein;-   p is 1, 2, 3 or 4;-   q is 0–12;-   each occurrence of S₁ is independently an aliphatic, alicyclic,    heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, or any    two adjacent S₁ moieties, taken together, may form an an alicyclic,    heteroalicyclic, aryl or heteroaryl moiety;-   R_(8b) and R_(9b) are each independently absent, hydrogen,    —(C═O)R_(L) or an aliphatic, alicyclic, heteroaliphatic,    heteroalicyclic, aryl or heteroaryl moiety, wherein each occurrence    of R_(L) is independently hydrogen, OH, OR_(M), or an aliphatic,    alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl    moiety, or wherein R_(8b) and R_(9b), taken together, form a    alicyclic or heteroalicyclic moiety, or an aryl or heteroaryl    moiety; wherein R_(M) is an aliphatic, alicyclic, heteroaliphatic,    heteroalicyclic, aryl or heteroaryl moiety; and-   NR₇ and CR_(8b), and CR_(8b) and CR_(9b) are each independently    linked by a single or double bond as valency permits.

Another important subclass of class (Ic) includes those compounds havingthe structure of formula (Ic) in which X₂ is C═O; G, J and M are eachCH₂; j, l and m are each 1; R is—C(R_(8b))C(R_(9b))N(R_(10b))C(R_(11b))—; R₃ is hydrogen; and thecompound has the structure:

-   wherein R₂, R₅–R₇ and Q are defined in classes and subclasses    herein;-   g is 0, 1, 2 or 3;-   R_(L1) and R_(L2) are independently hydrogen or an aliphatic,    alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl    moiety;-   R_(8b), R_(9b), R_(10b) and R_(11b) are each independently absent,    hydrogen, —(C═O)R_(L) or an aliphatic, alicyclic, heteroaliphatic,    heteroalicyclic, aryl or heteroaryl moiety, wherein each occurrence    of R_(L) is independently hydrogen, OH, OR_(M), or an aliphatic,    alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl    moiety, or wherein any two adjacent R_(8b), R_(9b), R_(10b) and    R_(11b) groups, taken together, form a alicyclic or heteroalicyclic    moiety, or an aryl or heteroaryl moiety; wherein R_(M) is an    aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or    heteroaryl moiety; and-   NR₇ and CR_(8b), CR_(9b) and CR_(9b), CR_(9b) and NR_(10b), NR_(10b)    and CR_(11b) are each independently linked by a single or double    bond as valency permits.

Another important subclass of class (Ic) includes those compounds havingthe structure of formula (Ic) in which X₂ is C═O; G, J and M are eachCH₂; j, l and m are each 1; R is—C(R_(8b))C(R_(9b))N(R_(10b))C(R_(11b))—; R₃ is hydrogen; R_(10b) andR_(11b), taken together, form a cyclic heteroalkyl group; and thecompound has the structure:

-   wherein R₂, R₅–R₇ and Q are defined in classes and subclasses    herein;-   p is 1, 2, 3 or 4;-   q is 0–12;-   g is 0, 1, 2 or 3;-   R_(L1) and R_(L2) are independently hydrogen or an aliphatic,    alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl    moiety;-   each occurrence of S₁ is independently an aliphatic, alicyclic,    heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, or any    two adjacent S₁ moieties, taken together, may form an an alicyclic,    heteroalicyclic, aryl or heteroaryl moiety;-   R_(8b) and R_(9b) are each independently hydrogen, —(C═O)R_(L) or an    aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or    heteroaryl moiety, wherein each occurrence of R_(L) is independently    hydrogen, OH, OR_(M), or an aliphatic, alicyclic, heteroaliphatic,    heteroalicyclic, aryl or heteroaryl moiety, or wherein R_(8b) and    R_(9b), taken together, form a alicyclic or heteroalicyclic moiety,    or an aryl or heteroaryl moiety; wherein R_(M) is an aliphatic,    alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl    moiety; and-   NR₇ and CR_(8b), and CR_(8b) and CR_(9b) are each independently    linked by a single or double bond as valency permits.

Another important subclass of class (Ic) includes those compounds havingthe structure of formula (Ic) in which X₂ is C═O; R is—C(R_(8c))C(R_(9c))C(R_(10c))C(R_(11c))OC(R_(12c))—; j is 0; l and m areeach 1; R₃ is hydrogen; G is CHR_(G1), M is CR_(M1)R_(M2); and thecompound has the following structure:

-   wherein R₁, R₂, R₅–R₇ and Q are defined in classes and subclasses    herein;-   g is 1, 2 or 3;-   L is CR_(L1)R_(L2), S, O or NR_(L3), wherein each occurrence of    R_(L1), R_(L2) and R_(L3) is independently hydrogen or an aliphatic,    alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl    moiety;-   each occurrence of R_(G1), R_(M1) and R_(M2) is independently    hydrogen or an aliphatic, alicyclic, heteroaliphatic,    heteroalicyclic, aryl or heteroaryl moiety;-   any two adjacent R_(L1), R_(L2), R_(L3), R_(G1), R_(M1) or R_(M2)    groups, taken together, may form a substituted or unsubstituted    alicyclic or heteroalicyclic moiety containing 3–6 atoms or an aryl    or heteroaryl moiety;-   R_(8c), R_(9c), R_(10c), R_(11c) and R_(12c) are each independently    absent, hydrogen, —(C═O)R_(L) or an aliphatic, alicyclic,    heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, wherein    each occurrence of R_(L) is independently hydrogen, OH, OR_(M), or    an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or    heteroaryl moiety, or wherein any two R_(8c), R_(9c), R_(10c),    R_(11c) and R_(12c) groups, taken together, form a alicyclic or    heteroalicyclic moiety, or an aryl or heteroaryl moiety; wherein    R_(M) is an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic,    aryl or heteroaryl moiety; and-   NR₇ and CR_(9c), CR_(8c) and CR_(9c), CR_(9c) and CR_(10c), and    CR_(10c) and CR_(11c) are each independently linked by a single or    double bond as valency permits.

Another important subclass of class (Ic) includes those compounds havingthe structure of formula (Ic) in which X₂ is C═O; R is—C(R_(8c))C(R_(9c))C(R_(10c))C(R_(11c))OC(R_(12c))—; G, J and M are eachCH₂; j, l and m are each 1; R₃ is hydrogen; and the compound has thefollowing structure:

-   wherein R₁, R₂, R₅–R₇ and Q are defined in classes and subclasses    herein;-   g is 0, 1, 2 or 3;-   R_(L1) and R_(L2) are independently hydrogen or an aliphatic,    alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl    moiety;-   R_(8c), R_(9c), R_(10c), R_(11c) and R_(12c) are each independently    absent, hydrogen, —(C═O)R_(L) or an aliphatic, alicyclic,    heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, wherein    each occurrence of R_(L) is independently hydrogen, OH, OR_(M), or    an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or    heteroaryl moiety, or wherein any two R_(8c), R_(9c), R_(10c),    R_(11c) and R_(12c) groups, taken together, form a alicyclic or    heteroalicyclic moiety, or an aryl or heteroaryl moiety; wherein    R_(M) is an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic,    aryl or heteroaryl moiety; and-   NR₇ and CR_(8c), CR_(8c) and CR_(9c), CR_(9c) and CR_(10c), and    CR_(10c) and CR_(11c) are each independently linked by a single or    double bond as valency permits.

A number of important subclasses of each of the foregoing subclasses ofclass (Ic) deserve separate mention; these subclasses include subclassesof the foregoing subclasses of class (Ic) in which:

-   i-c. R₂ is hydrogen, or a substituted or unsubstituted, linear or    branched, cyclic or acyclic, or saturated or unsaturated lower    alkyl, heteroalkyl, -alkyl(aryl) or acyl moiety;-   ii-c. R₂ is substituted or unsusbtituted, linear or branched, cyclic    or acyclic, saturated or unsaturated lower alkyl, heteroalkyl,    -alkyl(aryl) or acyl;-   iii-c. R₂ is substituted or unsusbtituted, linear or branched,    cyclic or acyclic, saturated or unsaturated lower alkyl;-   iv-c. R₂ is methyl, ethyl, propyl, butyl, pentyl, tert-butyl,    i-propyl, —CH(CH₃)CH₂CH₃, —CH(CH₃)CH₂CH₂CH₃, —CH₂CH(CH₃)₂,    —CH(CH₃)CH(CH₃)₂, —CH(CH₃)₂CH₂CH₃, —CH(CH₃)cyclobutyl, —CH(Et)₂,    —CH(CH₃)₂C CH, cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl;-   v-c. R₂ is hydrogen;-   vi-c. R₂ is hydrogen, methyl or benzyl;-   vii-c. R₂ is methyl;-   viii-c. R₂ is acyl, wherein the acyl group is a nitrogen proteting    group;-   ix-c. R₃ is hydrogen;-   x-c. R₁ and R₄, taken together, form a substituted or unsubstituted    pyrrolidine group;-   xi-c. R₁ and R₄, taken together, form a substituted or unsubstituted    piperidine group;-   xii-c. R₁ and R₄, taken together, form a substituted or    unsubstituted thiazolidine group;-   xiii-c. R₁ and R₄, taken together, form a substituted or    unsubstituted morpholine group;-   xiv-c. R₁ and R₄, taken together, form a substituted or    unsubstituted thiomorpholine group;-   xv-c. R₁ and R₄, taken together, form a substituted or unsubstituted    indole group;-   xvi-c. R₅ is hydrogen;-   xvii-c. R₆ is substituted or unsubstituted, linear or branched,    cyclic or acyclic, or saturated or unsaturated lower alkyl;-   xviii-c. R₆ is methyl, ethyl, propyl, butyl, pentyl, tert-butyl,    i-propyl, —CH(CH₃)CH₂CH₃, —CH₂CH(CH₃)₂, cyclohexyl, cyclopentyl,    cyclobutyl or cyclopropyl;-   xix-c. R₆ is tert-butyl;-   xx-c. The R₆-bearing carbon atom is of S configuration;-   xxi-c. R₇ is substituted or unsubstituted, linear or branched,    cyclic or acyclic, or saturated or unsaturated lower alkyl;-   xxii-c. R₇ is methyl;-   xxiii-c. R is —CH(R_(8a))C(R_(9a))═C(R_(10a))—; and    -   a) R_(8a) is substituted or unsubstituted, linear or branched,        cyclic or acyclic, or saturated or unsaturated lower alkyl;    -   b) R_(8a) is iso-propyl;    -   c) The R_(8a)-bearing carbon atom is of S configuration;    -   d) R_(9a) is hydrogen or substituted or unsubstituted, linear or        branched, cyclic or acyclic, or saturated or unsaturated lower        alkyl;    -   e) R_(9a) is hydrogen;    -   f) R_(10a) is hydrogen or substituted or unsubstituted, linear        or branched, cyclic or acyclic, or saturated or unsaturated        lower alkyl; or    -   g) R_(10a) is methyl;-   xxiv-c. R is —C(R_(8b))C(R_(9b))N(R_(10b))CR_(11b)— and    -   a) R_(8b) is substituted or unsubstituted, linear or branched,        cyclic or acyclic, or saturated or unsaturated lower alkyl;    -   b) R_(8b) is iso-propyl;    -   c) The R_(8b)-bearing carbon atom is of S configuration;    -   d) R_(9b) is hydrogen or substituted or unsubstituted, linear or        branched, cyclic or acyclic, or saturated or unsaturated lower        alkyl;    -   e) R_(10b) is hydrogen, or a substituted or unsubstituted,        linear or branched, cyclic or acyclic, or saturated or        unsaturated lower alkyl or acyl moiety;    -   f) R_(10b) is hydrogen, methyl or acetyl;    -   g) R_(10b) and R_(11b), taken together, form a substituted or        unsubstituted pyrrolidine ring; or    -   h) R_(9b) and R_(11b), taken together, form a substituted or        unsubstituted thiazole ring;-   xxxv-d. R is —C(R_(8c))C(R_(9c))C(R_(10c))CR_(11c)OR_(12c)— and    -   a) R_(8c) is substituted or unsubstituted, linear or branched,        cyclic or acyclic, or saturated or unsaturated lower alkyl;    -   b) R_(8c) is iso-propyl;    -   c) The R_(8c)-bearing carbon atom is of S configuration;    -   d) R_(9c) and R_(10c) are each independently hydrogen or        substituted or unsubstituted, linear or branched, cyclic or        acyclic, or saturated or unsaturated lower alkyl;    -   e) CR_(9c) and CR_(10c) are linked via a double bond;    -   f) CR_(9c) and CR_(10c) are linked via a double bond and R_(9c)        is hydrogen; or    -   g) CR_(9c) and CR_(10c) are linked via a double bond and R_(10c)        is methyl;-   xxv-c. —C(R₃)(R₄)N(R₁)(R₂) together represent the moiety having the    structure:

-   -   a) R₂ is hydrogen, or a substituted or unsubstituted, linear or        branched, cyclic or acyclic, or saturated or unsaturated lower        alkyl, heteroalkyl, -alkyl(aryl) or acyl moiety;    -   b) R₂ is methyl, ethyl or propyl;    -   c) R_(G1) is hydrogen, substituted or unsubstituted, linear or        branched, cyclic or acyclic, or saturated or unsaturated lower        alkyl or substituted or unsubstituted phenyl;    -   d) R_(G1) is hydrogen, methyl or phenyl;    -   e) R_(G1) and the substituents on L, taken together, form a        substituted or unsubstituted phenyl group;    -   f) R_(M1) and R_(M2) are each independently hydrogen, hydroxyl,        a substituted or unsubstituted, linear or branched, cyclic or        acyclic, or saturated or unsaturated lower alkyl moiety; a        substituted or unsubstituted phenyl moiety, or R_(M2) is absent        when R_(M1) and the substitutents on L, taken together, form a        substituted or unsubstituted aryl or heteroaryl moiety;    -   g) g is 1 or 2; or    -   h) L is CH₂, S or O;

-   xxvi-c. —C(R₃)(R₄)N(R₁)(R₂) together represent the moiety having the    structure:

-   -   a) R₂ is hydrogen, or a substituted or unsubstituted, linear or        branched, cyclic or acyclic, or saturated or unsaturated lower        alkyl, heteroalkyl, -alkyl(aryl) or acyl moiety;    -   b) R₂ is methyl;    -   c) R_(L1) and R_(L2) are each independently hydrogen,        substituted or unsubstituted, linear or branched, cyclic or        acyclic, or saturated or unsaturated lower alkyl or substituted        or unsubstituted phenyl;    -   d) R_(L1) and R_(L2) are each hydrogen;    -   e) R_(L1) and R_(L2) are each substituted or unsubstituted,        linear or branched, cyclic or acyclic, or saturated or        unsaturated lower alkyl; or    -   f) g is 1 or 2;

-   xxvii-c. X₂ is C═O;

-   xxviii-c. X₂ is CH₂;

-   xxix-c. X₂ is SO₂;

-   xxx-c. Q is OR^(Q′), SR^(Q′), NR^(Q′)R^(Q″), N₃, ═N—OH, or a moiety    selected from the group consisting of:

-   -   wherein each occurrence of r is 0, 1 or 2; s and t are        independently an integer from 0–8; X is O, S, or NR^(K); each        occurrence of R^(Q1) and R^(Q2) is independently hydrogen,        halogen, —CN, —S(O)_(h)R^(J), —NO₂, —COR^(J), —COR^(J),        —NR^(J)COR^(J), —NR^(J)CO₂R^(J), —CONR^(J)R^(J),        —CO(NOR^(J))R^(J), aliphatic, alicyclic, heteroaliphatic,        heteroalicyclic, aryl or heteroaryl moiety, or -Z₁R^(J); wherein        h is 1 or 2; and Z₁ is independently —O—, —S—, NR^(K), —C(O)—,        wherein each occurrence of R^(J) and R^(K) is independently        hydrogen, COR^(L), COOR^(L), CONR^(L)R^(M), —NR^(L)R^(M),        —S(O)₂R^(L), or an aliphatic, alicyclic, heteroaliphatic,        heteroalicyclic, aryl or heteroaryl moiety, and wherein each        occurrence of R_(L) and R_(M) is independently hydrogen, or an        aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or        heteroaryl moiety; and R^(Q′ and R) ^(Q″) are independently        hydrogen, or a substituted or unsubstituted, linear or branched,        cyclic or acyclic alkyl or heteroalkyl moiety, or a substituted        or unsubstituted aryl or heteroaryl moiety; or R^(Q′) and        R^(Q″), taken together with the nitrogen atom to which they are        attached, form a substituted or unsubstituted heterocyclic, aryl        or heteroaryl moiety;

-   xxxi-c. Q is OR^(Q′), SR^(Q′), NR^(Q′)R^(Q″), N₃, ═N—OH, or a moiety    selected from the group consisting of:

-   -   wherein each occurrence of r is 0, 1 or 2; s and t are        independently an integer from 0–8; each occurrence of R^(Q1) and        R^(Q2) is independently hydrogen, or a substituted or        unsubstituted, linear or branched, cyclic or acyclic alkyl or        heteroalkyl moiety, or a substituted or unsubstituted aryl or        heteroaryl moiety; or R^(Q1) and R^(Q2), taken together with the        nitrogen atom to which they are attached, form a substituted or        unsubstituted heterocyclic moiety; and R^(Q′) and R^(Q″) are        independently hydrogen, or a substituted or unsubstituted,        linear or branched, cyclic or acyclic alkyl or heteroalkyl        moiety, or a substituted or unsubstituted aryl or heteroaryl        moiety; or R^(Q′) and R^(Q″), taken together with the nitrogen        atom to which they are attached, form a substituted or        unsubstituted heterocyclic, aryl or heteroaryl moiety; and/or

-   xxxii-c. Q is OR^(Q′), SR^(Q′), NR^(Q′)R^(Q″), N₃, ═N—OH, or a    moiety selected from the group consisting of:

-   -   wherein each occurrence of r is 0, 1 or 2; and R^(Q′) and R^(Q″)        are independently hydrogen, or a substituted or unsubstituted,        linear or branched, cyclic or acyclic alkyl or heteroalkyl        moiety, or a substituted or unsubstituted aryl or heteroaryl        moiety; or R^(Q′) and R^(Q″), taken together with the nitrogen        atom to which they are attached, form a substituted or        unsubstituted heterocyclic, aryl or heteroaryl moiety.

An important subclass of class (Id) includes those compounds having thestructure of formula (Id) in which R is—CH(R_(8a))C(R_(9a))═C(R_(10a))—; X₂ is C═O; and the compound has thefollowing structure:

-   wherein R₃ and R₄ are each independently an aliphatic, alicyclic,    heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, or,    when taken together, form an alicyclic, heteroalicyclic,    alicyclic(aryl), heteroalicyclic(aryl), alicyclic(heteroaryl) or    heteroalicyclic(heteroaryl) moiety, R₁, R₂, R₅–R₇ and Q are defined    in classes and subclasses herein; and-   R_(8a), R_(9a) and R_(10a) are each independently hydrogen, or an    aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or    heteroaryl moiety; and wherein any two R₇, R_(8a), R_(9a) and    R_(10a) groups may form an alicyclic, heteroalicyclic,    alicyclicc(aryl), heteroalicyclic(aryl), alicyclic(heteroaryl) or    heteroalicyclic(heteroaryl) moiety, or an aryl or heteroaryl moiety.

Another important subclass of class (Id) includes those compounds havingthe structure of formula (Id) in which R is—C(R_(8b))C(R_(9b))N(R_(10b))C(R_(11b))—; X₂ is C═O; and the compoundhas the following structure:

-   wherein R₃ and R₄ are each independently an aliphatic, alicyclic,    heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, or,    when taken together, form an alicyclic, heteroalicyclic,    alicyclic(aryl), heteroalicyclic(aryl), alicyclic(heteroaryl) or    heteroalicyclic(heteroaryl) moiety; R₁, R₂, R₅–R₇ and Q are defined    in classes and subclasses herein;-   R_(8b), R_(9b), R_(10b) and R_(11b) are each independently absent,    hydrogen, —(C═O)R_(L) or an aliphatic, alicyclic, heteroaliphatic,    heteroalicyclic, aryl or heteroaryl moiety, wherein each occurrence    of R_(L) is independently hydrogen, OH, OR_(M), or an aliphatic,    alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl    moiety, or wherein any two R_(8b), R_(9b), R_(10b) and R_(11b)    groups, taken together, form a alicyclic or heteroalicyclic moiety,    or an aryl or heteroaryl moiety; wherein R_(M) is an aliphatic,    alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl    moiety; and-   NR₇ and CR_(9b), CR_(8b) and CR_(9b), CR_(9b) and NR_(10b), NR_(10b)    and CR_(11b) are independently linked by a single or double bond as    valency permits.

Another important subclass of class (Id) includes those compounds havingthe structure of formula (Id) in which R is—C(R_(8b))C(R_(9b))N(R_(10b))C(R_(11b))—; X₂ is C═O; R_(10b) andR_(11b), taken together, form a cyclic heteroalkyl group; and thecompound has the following structure:

wherein R₃ and R₄ are each independently an aliphatic, alicyclic,heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, or, whentaken together, form an alicyclic, heteroalicyclic, alicyclic(aryl),heteroalicyclic(aryl), alicyclic(heteroaryl) orheteroalicyclic(heteroaryl) moiety; R₁, R₂, R₅–R₇ and Q are defined inclasses and subclasses herein;

-   p is 1, 2, 3 or 4;-   q is 0–12;-   each occurrence of S₁ is independently an aliphatic, alicyclic,    heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, or any    two adjacent S₁ moieties, taken together, may form an an alicyclic,    heteroalicyclic, aryl or heteroaryl moiety;-   R_(8b) and R_(9b) are each independently hydrogen, —(C═O)R_(L) or an    aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or    heteroaryl moiety, wherein each occurrence of R_(L) is independently    hydrogen, OH, OR_(M), or an aliphatic, alicyclic, heteroaliphatic,    heteroalicyclic, aryl or heteroaryl moiety, or wherein R_(8b) and    R_(9b), taken together, form a alicyclic or heteroalicyclic moiety,    or an aryl or heteroaryl moiety; wherein R_(M) is an aliphatic,    alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl    moiety; and-   NR₇ and CR₈, and CR_(8b) and CR_(9b) are independently linked by a    single or double bond as valency permits.

Another important subclass of class (Id) includes those compounds havingthe structure of formula (Id) in which X₂ is C═O; R is—C(R_(8c))C(R_(9c))C(R_(10c))C(R_(11c))OC(R_(12c))—; and the compoundhas the following structure:

wherein R₃ and R₄ are each independently an aliphatic, alicyclic,heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, or, whentaken together, form an alicyclic, heteroalicyclic, alicyclic(aryl),heteroalicyclic(aryl), alicyclic(heteroaryl) orheteroalicyclic(heteroaryl) moiety; R₁, R₂, R₅–R₇ and Q are defined inclasses and subclasses herein;

-   R_(8c), R_(9c), R_(10c), R_(11c) and R_(12c) are each independently    absent, hydrogen, (C═O)R_(L) or an aliphatic, alicyclic,    heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, wherein    each occurrence of R_(L) is independently hydrogen, OH, OR_(M), or    an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or    heteroaryl moiety, or wherein any two R_(8c), R_(9c), R_(10c),    R_(11c) and R_(12c) groups, taken together, form a alicyclic or    heteroalicyclic moiety, or an aryl or heteroaryl moiety; wherein    R_(M) is an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic,    aryl or heteroaryl moiety; and-   NR₇ and CR_(8c), CR_(8c) and CR_(9c), CR_(9c) and CR_(10c), and    CR_(10c) and CR_(11c) are each independently linked by a single or    double bond as valency permits.

A number of important subclasses of each of the foregoing subclasses ofclass (Id) deserve separate mention; these subclasses include subclassesof the foregoing subclasses of class (Id) in which:

-   i-d. R₁ and R₂ are independently hydrogen or substituted or    unsubstituted, linear or branched, cyclic or acyclic, or saturated    or unsaturated lower alkyl, heteroalkyl, -alkyl(aryl) or acyl;-   ii-d. R₁ is hydrogen and R₂ is substituted or unsusbtituted, linear    or branched, cyclic or acyclic, saturated or unsaturated lower    alkyl, heteroalkyl, -alkyl(aryl) or acyl;-   iii-d. R₁ is hydrogen and R₂ is substituted or unsusbtituted, linear    or branched, cyclic or acyclic, saturated or unsaturated lower    alkyl;-   iv-d. R₁ is hydrogen and R₂ is methyl, ethyl, propyl, butyl, pentyl,    tert-butyl, i-propyl, —CH(CH₃)CH₂CH₃; —CH(CH₃)CH₂CH₂CH₃,    —CH₂CH(CH₃)₂, —CH(CH₃)CH(CH₃)₂, —CH(CH₃)₂CH₂CH₃, —CH(CH₃)cyclobutyl,    —CH(Et)₂, —CH(CH₃)₂C CH, cyclohexyl, cyclopentyl, cyclobutyl or    cyclopropyl;-   v-d. R₁ and R₂ are each hydrogen;-   vi-d. R₁ and R₂ are independently hydrogen or methyl;-   vii-d. R₁ and R₂ are each methyl;-   viii-d. R₃ and R₄ are each independently substituted or    unsubstituted, linear or branched, cyclic or acyclic, or saturated    or unsaturated lower alkyl, heteroalkyl or -alkyl(aryl) or    substituted or unsubstituted aryl or heteroaryl;-   ix-d. R₃ and R₄ are each independently substituted or unsubstituted,    linear or branched, cyclic or acyclic, or saturated or unsaturated    lower alkyl, -alkyl(aryl) or substituted or unsubstituted aryl;-   x-d. R₃ and R₄ are each independently substituted or unsubstituted    lower alkyl, aryl or heteroaryl;-   xi-d. R₃ and R₄ are each independently methyl, ethyl, propyl, butyl,    pentyl, tert-butyl, i-propyl, —CH(CH₃)CH₂CH₃, —CH(CH₃)CH₂CH₂CH₃,    —CH₂CH(CH₃)₂, —CH(CH₃)CH(CH₃)₂, —CH(CH₃)₂CH₂CH₃, —CH(CH₃)cyclobutyl,    —CH(Et)₂, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, phenyl,    —C₁₋₆alkylOR^(a), —C₁₋₆alkylSR^(a) or —CR^(a)R^(b)R^(c); wherein    R^(a) and R^(b) are independently hydrogen, substituted or    unsubstituted, linear or branched, cyclic or acyclic, or saturated    or unsaturated lower alkyl and R^(c) is substituted or unsubstituted    aryl or heteroaryl;-   xii-d. R₃ and R₄ are each independently methyl, ethyl, propyl,    butyl, pentyl, tert-butyl, i-propyl, —CH(CH₃)CH₂CH₃,    —CH(CH₃)CH₂CH₂CH₃, —CH₂CH(CH₃)₂, —CH(CH₃)CH(CH₃)₂, —CH(CH₃)₂CH₂CH₃,    —CH(CH₃)cyclobutyl, —CH(Et)₂, cyclohexyl, cyclopentyl, cyclobutyl,    cyclopropyl, phenyl, —C₁₋₆alkylO^(a), —C₁₋₆alkylSR^(a) or    —CR^(b)R^(c)Ph; wherein R^(a) is hydrogen, substituted or    unsubstituted, linear or branched, cyclic or acyclic, or saturated    or unsaturated lower alkyl and R^(b) And R^(c) are each    independently substituted or unsubstituted linear or branched,    cyclic or acyclic, or saturated or unsaturated lower alkyl;-   xiii-d. R₃ and R₄ are each ethyl;-   xiv-d. R₃ is phenyl and R₄ is lower alkyl;-   xv-d. R₃ is phenyl and R₄ is ethyl;-   xvi-d. R₃ and R₄, taken together, form a substituted or    unsubstituted cycloalkyl group;-   xvii-d. R₃ and R₄, taken together, form a cyclohexyl group;-   xviii-d. R₃ and R₄, taken together, form a substituted or    unsubstituted cycloalkyl(aryl) group;-   xix-d. R₅ is hydrogen;-   xx-d. R₆ is substituted or unsubstituted, linear or branched, cyclic    or acyclic, or saturated or unsaturated lower alkyl;-   xxi-d. R₆ is methyl, ethyl, propyl, butyl, pentyl, tert-butyl,    i-propyl, —CH(CH₃)CH₂CH₃, —CH₂CH(CH₃)₂, cyclohexyl, cyclopentyl,    cyclobutyl or cyclopropyl;-   xxii-d. R₆ is tert-butyl;-   xxiii-d. The R₆-bearing carbon atom is of S configuration;-   xxiv-d. R₇ is substituted or unsubstituted, linear or branched,    cyclic or acyclic, or saturated or unsaturated lower alkyl;-   xxv-d. R₇ is methyl;-   xxvi-d. R is —CH(R_(8a))C(R_(9a))═C(R_(10a))—; and    -   i) R_(8a) is substituted or unsubstituted, linear or branched,        cyclic or acyclic, or saturated or unsaturated lower alkyl;    -   j) R_(8a) is iso-propyl;    -   k) The R_(8a)-bearing carbon atom is of S configuration;    -   l) R_(9a) is hydrogen or substituted or unsubstituted, linear or        branched, cyclic or acyclic, or saturated or unsaturated lower        alkyl;    -   m) R_(9a) is hydrogen;    -   n) R_(10a) is hydrogen or substituted or unsubstituted, linear        or branched, cyclic or acyclic, or saturated or unsaturated        lower alkyl; or    -   o) R_(10a) is methyl;-   xxvii-d. R is —C(R_(8b))C(R_(9b))N(R_(10b))CR_(11b)— and    -   p) R_(8b) is substituted or unsubstituted, linear or branched,        cyclic or acyclic, or saturated or unsaturated lower alkyl;    -   q) R_(8b) is iso-propyl;    -   r) The R_(8b)-bearing carbon atom is of S configuration;    -   s) R_(9b) is hydrogen or substituted or unsubstituted, linear or        branched, cyclic or acyclic, or saturated or unsaturated lower        alkyl;    -   t) R_(10b) is hydrogen, or a substituted or unsubstituted,        linear or branched, cyclic or acyclic, or saturated or        unsaturated lower alkyl or acyl moiety;    -   u) R_(10b) is hydrogen, methyl or acetyl;    -   v) R_(10b) and R_(11b), taken together, form a substituted or        unsubstituted pyrrolidine ring; or    -   w) R_(9b) and R_(11b), taken together, form a substituted or        unsubstituted thiazole ring;-   xxviii-d. R is —C(R_(8c))C(R_(9c))C(R_(10c))CR_(11c)OCR_(12c)— and    -   h) R_(8c) is substituted or unsubstituted, linear or branched,        cyclic or acyclic, or saturated or unsaturated lower alkyl;    -   i) R_(8c) is iso-propyl;    -   j) The R_(8c)-bearing carbon atom is of S configuration;    -   k) R_(9c) and R_(10c) are each independently hydrogen or        substituted or unsubstituted, linear or branched, cyclic or        acyclic, or saturated or unsaturated lower alkyl;    -   l) CR_(9c) and CR_(10c) are linked via a double bond;    -   m) CR_(9c) and CR_(10c) are linked via a double bond and R_(9c)        is hydrogen; or    -   n) CR_(9c) and CR_(10c) are linked via a double bond and R_(10c)        is methyl;-   xxix-d. X₂ is C═O;-   xxx-d. X₂ is CH₂;-   xxxi-d. X₂ is SO₂;-   xxxii-d. Q is OR^(Q′), SR^(Q′), NR^(Q′)R^(Q″), N₃, ═N—OH, or a    moiety selected from the group consisting of:

-   -   wherein each occurrence of r is 0, 1 or 2; s and t are        independently an integer from 0–8; X is O, S, or NR^(K); each        occurrence of R^(Q1) and R^(Q2) is independently hydrogen,        halogen, —CN, —S(O)_(h)R^(J), —NO₂, —COR^(J), —CO₂R^(J),        —NR^(J)COR^(J), —NR^(J)CO₂R^(J), —CONR^(J)R^(J),        —CO(NOR^(J))R^(J), aliphatic, alicyclic, heteroaliphatic,        heteroalicyclic, aryl or heteroaryl moiety, or -Z₁R^(J); wherein        h is 1 or 2; and Z₁ is independently —O—, —S—, NR^(K), —C(O)—,        wherein each occurrence of R₁ and R^(K) is independently        hydrogen, COR^(L), COOR^(L), CONR^(L)R^(M), —NR^(L)R^(M),        —S(O)₂R^(L), or an aliphatic, alicyclic, heteroaliphatic,        heteroalicyclic, aryl or heteroaryl moiety, and wherein each        occurrence of R_(L) and R_(M) is independently hydrogen, or an        aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or        heteroaryl moiety; and R^(Q′) and R^(Q″) are independently        hydrogen, or a substituted or unsubstituted, linear or branched,        cyclic or acyclic alkyl or heteroalkyl moiety, or a substituted        or unsubstituted aryl or heteroaryl moiety; or R^(Q′) and        R^(Q″), taken together with the nitrogen atom to which they are        attached, form a substituted or unsubstituted heterocyclic, aryl        or heteroaryl moiety;

-   xxxiii-d. Q is OR^(Q′), SR^(Q′), NR^(Q′)R^(Q″), N₃, ═N—OH, or a    moiety selected from the group consisting of:

-   -   wherein each occurrence of r is 0, 1 or 2; s and t are        independently an integer from 0–8; each occurrence of R^(Q1) and        R^(Q2) is independently hydrogen, or a substituted or        unsubstituted, linear or branched, cyclic or acyclic alkyl or        heteroalkyl moiety, or a substituted or unsubstituted aryl or        heteroaryl moiety; or R^(Q1) and R^(Q2), taken together with the        nitrogen atom to which they are attached, form a substituted or        unsubstituted heterocyclic moiety; and R^(Q′) and R^(Q″) are        independently hydrogen, or a substituted or unsubstituted,        linear or branched, cyclic or acyclic alkyl or heteroalkyl        moiety, or a substituted or unsubstituted aryl or heteroaryl        moiety; or R^(Q′) and R^(Q″), taken together with the nitrogen        atom to which they are attached, form a substituted or        unsubstituted heterocyclic, aryl or heteroaryl moiety; and/or

-   xxxiv-d. Q is OR^(Q′), SR^(Q′), NR^(Q′)R^(Q″), N₃, ═N—OH, —N—OH, or    a moiety selected from the group consisting of:

-   -   wherein each occurrence of r is 0, 1 or 2; and R^(Q′) and R^(Q″)        are independently hydrogen, or a substituted or unsubstituted,        linear or branched, cyclic or acyclic alkyl or heteroalkyl        moiety, or a substituted or unsubstituted aryl or heteroaryl        moiety; or R^(Q′) and R^(Q″), taken together with the nitrogen        atom to which they are attached, form a substituted or        unsubstituted heterocyclic, aryl or heteroaryl moiety.

As the reader will appreciate, compounds of particular interest include,among others, those which share the attributes of one or more of theforegoing subclasses. Some of those subclasses are illustrated by thefollowing sorts of compounds:

I) Compounds of the Formula (and Pharmaceutically Acceptable DerivativesThereof):

wherein R₁–R₂, R_(4a), R_(4b), R_(9a)–R_(10a) and Q are as defined aboveand in subclasses herein; and Ar is a substituted or unsubstitued arylor heteroaryl moiety.

II) Compounds of the Formula (and Pharmaceutically AcceptableDerivatives Thereof):

wherein A, B, D, E, a, b, d, e, R₁–R₂, R_(4a), R_(4b), andR_(9a)–R_(10a) are as defined above and in subclasses herein; and Ar isa substituted or unsubstitued aryl or heteroaryl moiety.

It will also be appreciated that for each of the subgroups I–IIdescribed above, a variety of other subclasses are of special interest,including, but not limited to those classes i-a. through xliv-a.described above and classes, subclasses and species of compoundsdescribed above and in the examples herein.

III) Compounds of the Formula (and Pharmaceutically AcceptableDerivatives Thereof):

wherein R₁–R₂, R_(4a), R_(4b), R_(9b)–R_(11b) and R_(G) are as definedabove and in subclasses herein; and Ar is a substituted or unsubstituedaryl or heteroaryl moiety.

IV) Compounds of the Formula (and Pharmaceutically AcceptableDerivatives Thereof):

wherein A, B, D, E, a, b, d, e, R₁–R₂, R_(4a), R_(4b), andR_(9b)–R_(11b) are as defined above and in subclasses herein; and Ar isa substituted or unsubstitued aryl or heteroaryl moiety.

V) Compounds of the Formula (and Pharmaceutically Acceptable DerivativesThereof):

wherein R₁–R₂, R_(4a), R_(4b), R_(9a)–R_(12c) and R_(G) are as definedabove and in subclasses herein; and Ar is a substituted or unsubstituedaryl or heteroaryl moiety.

It will also be appreciated that for each of the subgroups III–Vdescribed above, a variety of other subclasses are of special interest,including, but not limited to those classes i-b. through xlii-b.described above and classes, subclasses and species of compoundsdescribed above and in the examples herein.

VI) Compounds of the Formula (and Pharmaceutically AcceptableDerivatives Thereof):

wherein L, R_(9a)–R_(10a), R_(G1), R_(M1) and R_(M2) are as definedabove and in subclasses herein; g is 1 or 2; Q is OR^(Q′), whereinR^(Q′) is hydrogen or lower alkyl; and R₂ and R₆ are independentlysubstituted or unsubstituted linear or branched lower alkyl.

VII) Compounds of the Formula (and Pharmaceutically AcceptableDerivatives Thereof):

wherein g, R_(9a)–R_(10a), R_(L1) and R_(L2) are as defined above and insubclasses herein; X₁ is CH₂ or C═O; R₂ and R₆ are independentlysubstituted or unsubstituted linear or branched lower alkyl; and Q isOR^(Q′) or NR^(Q′)R^(Q″) wherein R^(Q′) is hydrogen or lower alkyl, orR^(Q′) and R^(Q″), taken together with the nitrogen atom to which theyare attached, form a substituted or unsubstituted heterocyclic moiety,whereby each of the foregoing alkyl moieties may be substituted orunsubstituted, linear or branched, cyclic or acyclic.

VIII) Compounds of the Formula (and Pharmaceutically AcceptableDerivatives Thereof):

wherein A, B, D, E, L, a, b, d, e, p, R_(9b), R^(G1), R^(M1) and R_(M2)are as defined above and in subclasses herein; g is 1 or 2; and R₂ andR₆ are independently substituted or unsubstituted linear or branchedlower alkyl.

IX) Compounds of the Formula (and Pharmaceutically AcceptableDerivatives Thereof):

wherein p, R_(9b), R_(L1), R_(L2), R^(Q′) and R^(Q″) are as definedabove and in subclasses herein; and R₂ and R₆ are independentlysubstituted or unsubstituted linear or branched lower alkyl.

It will also be appreciated that for each of the subgroups VI–IXdescribed above, a variety of other subclasses are of special interest,including, but not limited to those classes i-c. through xxxii-c.described above and classes, subclasses and species of compoundsdescribed above and in the examples herein. In certain embodiments, forcompounds of subgroups VI–IX above, R₂ is methyl, iso-propyl, sec-butylor —CH(CH₃)CH(CH₃)₂. In certain embodiments, for compounds of subgroupsVI–IX above, R₆ is tert-butyl or iso-propyl. In certain embodiments, forcompounds of subgroups VI–IX above, R₂ is methyl, iso-propyl, see-butylor —CH(CH₃)CH(CH₃)₂, and R₆ is tert-butyl or iso-propyl. In certainexemplary embodiments, for compounds of subgroups VI–IX above, R₂ ismethyl and R₆ is tert-butyl. In certain exemplary embodiments, forcompounds of subgroups VI–IX above, R₂ is iso-propyl and R₆ istert-butyl. In certain exemplary embodiments, for compounds of subgroupsVI–IX above, R₂ is sec-butyl and R₆ is tert-butyl or iso-propyl. Incertain exemplary embodiments, for compounds of subgroups VI–IX above,R₂ is —CH(CH₃)CH(CH₃)₂, and R₆ is tert-butyl.

X) Compounds of the Formula (and Pharmaceutically Acceptable DerivativesThereof):

wherein R₁, R_(9a), R_(10a) and R_(G) are as defined above and insubclasses herein; and R₃ and R₄ are each independently an alkyl,heteroalkyl, heteroalkyl(aryl) or alkyl(aryl) moiety, or R₃ and R₄,taken together, form a cyclic alkyl or heteroalkyl moiety.

It will also be appreciated that for subgroup X described above, avariety of other subclasses are of special interest, including, but notlimited to those classes i-d. through xxxii-d. described above andclasses, subclasses and species of compounds described above and in theexamples herein.

Some of the foregoing compounds can comprise one or more asymmetriccenters, and thus can exist in various isomeric forms, e.g.,stereoisomers and/or diastereomers. It is to be understood that theinvention encompasses every possible isomer such as geometric isomer,optical isomer, stereoisomer and tautomer based on asymmetric carbon,which can occur in the structures of the inventive compounds, andmixtures of such isomers, and is not limited to the specificstereochemistry shown for the compounds disclosed in the presentspecification. It will be further appreciated that the absolutestereochemistry of some of the compounds recited in the Exemplificationherein has not been determined, and that when a stereochemistry wasassigned for those compounds it is meant to be tentative and to indicatethat a set of diastereomers exists for those compounds and/ot that adiastereomer was isolated in pure form. Thus, inventive compounds andpharmaceutical compositions thereof may be in the form of an individualenantiomer, diastereomer or geometric isomer, or may be in the form of amixture of stereoisomers. In certain embodiments, the compounds of theinvention are enantiopure compounds. In certain other embodiments,mixtures of stereoisomers or diastereomers are provided.

Furthermore, certain compounds, as described herein may have one or moredouble bonds that can exist as either the Z or E isomer, unlessotherwise indicated. The invention additionally encompasses thecompounds as individual isomers substantially free of other isomers andalternatively, as mixtures of various isomers, e.g., racemic mixtures ofstereoisomers. The invention also encompasses tautomers of specificcompounds as described above. In addition to the above-mentionedcompounds per se, this invention also encompasses pharmaceuticallyacceptable derivatives of these compounds and compositions comprisingone or more compounds of the invention and one or more pharmaceuticallyacceptable excipients or additives.

Compounds of the invention may be prepared by crystallization ofcompound of formula (I) under different conditions and may exist as oneor a combination of polymorphs of compound of general formula (I)forming part of this invention. For example, different polymorphs may beidentified and/or prepared using different solvents, or differentmixtures of solvents for recrystallization; by performingcrystallizations at different temperatures; or by using various modes ofcooling, ranging from very fast to very slow cooling duringcrystallizations. Polymorphs may also be obtained by heating or meltingthe compound followed by gradual or fast cooling. The presence ofpolymorphs may be determined by solid probe NMR spectroscopy, IRspectroscopy, differential scanning calorimetry, powder X-raydiffractogram and/or other techniques. Thus, the present inventionencompasses inventive compounds, their derivatives, their tautomericforms, their stereoisomers, their polymorphs, their pharmaceuticallyacceptable salts their pharmaceutically acceptable solvates andpharmaceutically acceptable compositions containing them.

2) Compounds and Definitions

As discussed above, this invention provides novel compounds with a rangeof biological properties. Compounds of this invention have biologicalactivities relevant for the treatment of diseases or other disorderssuch as proliferative diseases, including, but not limited to cancer. Incertain other embodiments, the inventive compounds also find use in theprevention of restenosis of blood vessels subject to traumas such asangioplasty and stenting.

Compounds of this invention include those specifically set forth aboveand described herein, and are illustrated in part by the variousclasses, subgenera and species disclosed elsewhere herein.

Additionally, the present invention provides pharmaceutically acceptablederivatives of the inventive compounds, and methods of treating asubject using these compounds, pharmaceutical compositions thereof, oreither of these in combination with one or more additional therapeuticagents. The phrase, “pharmaceutically acceptable derivative”, as usedherein, denotes any pharmaceutically acceptable salt, ester, or salt ofsuch ester, of such compound, or any other adduct or derivative which,upon administration to a patient, is capable of providing (directly orindirectly) a compound as otherwise described herein, or a metabolite orresidue thereof. Pharmaceutically acceptable derivatives thus includeamong others pro-drugs. A pro-drug is a derivative of a compound,usually with significantly reduced pharmacological activity, whichcontains an additional moiety which is susceptible to removal in vivoyielding the parent molecule as the pharmacologically active species. Anexample of a pro-drug is an ester which is cleaved in vivo to yield acompound of interest. Pro-drugs of a variety of compounds, and materialsand methods for derivatizing the parent compounds to create thepro-drugs, are known and may be adapted to the present invention.Certain exemplary pharmaceutical compositions and pharmaceuticallyacceptable derivatives will be discussed in more detail herein below.

Numerous suitable prodrug moieties, and information concerning theirselection, synthesis and use are well known in the art. Examples ofprodrug moieties of interest include, among others, prodrug moietiesthat can be attached to primary or secondary amine-containingfunctionalities. Examples of such prodrug moieties include thefollowing:

For the synthesis of the prodruggroups, see Borchardt, R. T. et. al.,J.Org. Chem. 1997, 43,3641–3652. R¹ = all natural, unnatural amino acids

For the synthesis of the prodruggroups, see Zhou, X-X. et. al.,PCT WO99/51613. R¹ = C1–C4 alkyl, cycloalkyl, oxyalkyl, aminoalkyl, etc. R² =all natural, unnatural amino acids

For the synthesis of the prodruggroups, see Ezra, A. et. al.,J. Med.Chem. 2000, 43,3641–3652. R¹, R² = all natural, unnatural amino acidsOther examples of prodrug moieties of interest include prodrug moietiesthat can be attached to hydroxyl-containing functionalities. Suchprodrug moieties a well-known in the art, and will be readily identifiedby a person skilled in the relevant art. The present inventionencompasses any prodrug form of the compounds described herein.

Certain compounds of the present invention, and definitions of specificfunctional groups are also described in more detail below. For purposesof this invention, the chemical elements are identified in accordancewith the Periodic Table of the Elements, CAS version, Handbook ofChemistry and Physics, 75^(th) Ed., inside cover, and specificfunctional groups are generally defined as described therein.Additionally, general principles of organic chemistry, as well asspecific functional moieties and reactivity, are described in “OrganicChemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999,the entire contents of which are incorporated herein by reference.Furthermore, it will be appreciated by one of ordinary skill in the artthat the synthetic methods, as described herein, utilize a variety ofprotecting groups. By the term “protecting group”, as used herein, it ismeant that a particular functional moiety, e.g., O, S, or N, istemporarily blocked so that a reaction can be carried out selectively atanother reactive site in a multifunctional compound. In preferredembodiments, a protecting group reacts selectively in good yield to givea protected substrate that is stable to the projected reactions; theprotecting group must be selectively removed in good yield by readilyavailable, preferably nontoxic reagents that do not attack the otherfunctional groups; the protecting group forms an easily separablederivative (more preferably without the generation of new stereogeniccenters); and the protecting group has a minimum of additionalfunctionality to avoid further sites of reaction. As detailed herein,oxygen, sulfur, nitrogen and carbon protecting groups may be utilized.For example, in certain embodiments, as detailed herein, certainexemplary oxygen protecting groups are utilized. These oxygen protectinggroups include, but are not limited to methyl ethers, substituted methylethers (e.g., MOM (methoxymethyl ether), MTM (methylthiomethyl ether),BOM (benzyloxymethyl ether), PMBM (p-methoxybenzyloxymethyl ether), toname a few), substituted ethyl ethers, substituted benzyl ethers, silylethers (e.g., TMS (trimethylsilyl ether), TES (triethylsilylether), TIPS(triisopropylsilyl ether), TBDMS (t-butyldimethylsilyl ether), tribenzylsilyl ether, TBDPS (t-butyldiphenyl silyl ether), to name a few), esters(e.g., formate, acetate, benzoate (Bz), trifluoroacetate,dichloroacetate, to name a few), carbonates, cyclic acetals and ketals.In certain other exemplary embodiments, nitrogen protecting groups areutilized. These nitrogen protecting groups include, but are not limitedto, carbamates (including methyl, ethyl and substituted ethyl carbamates(e.g., Troc), to name a few) amides, cyclic imide derivatives, N-Alkyland N-Aryl amines, imine derivatives, and enamine derivatives, to name afew. Certain other exemplary protecting groups are detailed herein,however, it will be appreciated that the present invention is notintended to be limited to these protecting groups; rather, a variety ofadditional equivalent protecting groups can be readily identified usingthe above criteria and utilized in the present invention. Additionally,a variety of protecting groups are described in “Protective Groups inOrganic Synthesis” Third Ed. Greene, T. W. and Wuts, P. G., Eds., JohnWiley & Sons, New York: 1999, the entire contents of which are herebyincorporated by reference.

It will be appreciated that the compounds, as described herein, may besubstituted with any number of substituents or functional moieties. Ingeneral, the term “substituted” whether preceded by the term“optionally” or not, and substituents contained in formulas of thisinvention, refer to the replacement of hydrogen radicals in a givenstructure with the radical of a specified substituent. When more thanone position in any given structure may be substituted with more thanone substituent selected from a specified group, the substituent may beeither the same or different at every position. As used herein, the term“substituted” is contemplated to include all permissible substituents oforganic compounds. In a broad aspect, the permissible substituentsinclude acyclic and cyclic, branched and unbranched, carbocyclic andheterocyclic, aromatic and nonaromatic substituents of organiccompounds. For purposes of this invention, heteroatoms such as nitrogenmay have hydrogen substituents and/or any permissible substituents oforganic compounds described herein which satisfy the valencies of theheteroatoms. Furthermore, this invention is not intended to be limitedin any manner by the permissible substituents of organic compounds.Combinations of substituents and variables envisioned by this inventionare preferably those that result in the formation of stable compoundsuseful in the treatment, for example of cancer. The term “stable”, asused herein, preferably refers to compounds which possess stabilitysufficient to allow manufacture and which maintain the integrity of thecompound for a sufficient period of time to be detected and preferablyfor a sufficient period of time to be useful for the purposes detailedherein.

The term “aliphatic”, as used herein, includes both saturated andunsaturated, straight chain (i.e., unbranched) or branched aliphatichydrocarbons, which are optionally substituted with one or morefunctional groups. As will be appreciated by one of ordinary skill inthe art, “aliphatic” is intended herein to include, but is not limitedto, alkyl, alkenyl, alkynyl moieties. Thus, as used herein, the term“alkyl” includes straight and branched alkyl groups. An analogousconvention applies to other generic terms such as “alkenyl”, “alkynyl”and the like. Furthermore, as used herein, the terms “alkyl”, “alkenyl”,“alkynyl” and the like encompass both substituted and unsubstitutedgroups. In certain embodiments, as used herein, “lower alkyl” is used toindicate those alkyl groups (cyclic, acyclic, substituted,unsubstituted, branched or unbranched) having 1–6 carbon atoms.

In certain embodiments, the alkyl, alkenyl and alkynyl groups employedin the invention contain 1–20 aliphatic carbon atoms. In certain otherembodiments, the alkyl, alkenyl, and alkynyl groups employed in theinvention contain 1–10 aliphatic carbon atoms. In yet other embodiments,the alkyl, alkenyl, and alkynyl groups employed in the invention contain1–8 aliphatic carbon atoms. In still other embodiments, the alkyl,alkenyl, and alkynyl groups employed in the invention contain 1–6aliphatic carbon atoms. In yet other embodiments, the alkyl, alkenyl,and alkynyl groups employed in the invention contain 1–4 carbon atoms.Illustrative aliphatic groups thus include, but are not limited to, forexample, methyl, ethyl, n-propyl, isopropyl, allyl, n-butyl, sec-butyl,isobutyl, tert-butyl, n-pentyl, sec-pentyl, isopentyl, tert-pentyl,n-hexyl, sec-hexyl, moieties and the like, which again, may bear one ormore substituents. Alkenyl groups include, but are not limited to, forexample, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and thelike. Representative alkynyl groups include, but are not limited to,ethynyl, 2-propynyl (propargyl), 1-propynyl and the like.

The term “alicyclic”, as used herein, refers to compounds which combinethe properties of aliphatic and cyclic compounds and include but are notlimited to cyclic, or polycyclic aliphatic hydrocarbons and bridgedcycloalkyl compounds, which are optionally substituted with one or morefunctional groups. As will be appreciated by one of ordinary skill inthe art, “alicyclic” is intended herein to include, but is not limitedto, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties, which areoptionally substituted with one or more functional groups. Illustrativealicyclic groups thus include, but are not limited to, for example,cyclopropyl, —CH₂-cyclopropyl, cyclobutyl, —CH₂-cyclobutyl, cyclopentyl,—CH₂-cyclopentyl-n, cyclohexyl, —CH₂-cyclohexyl, cyclohexenylethyl,cyclohexanylethyl, norborbyl moieties and the like, which again, maybear one or more substituents.

The term “alkoxy” (or “alkyloxy”), or “thioalkyl” as used herein refersto an alkyl group, as previously defined, attached to the parentmolecular moiety through an oxygen atom or through a sulfur atom. Incertain embodiments, the alkyl group contains 1–20 aliphatic carbonatoms. In certain other embodiments, the alkyl group contains 1–10aliphatic carbon atoms. In yet other embodiments, the alkyl, alkenyl,and alkynyl groups employed in the invention contain 1–8 aliphaticcarbon atoms. In still other embodiments, the alkyl group contains 1–6aliphatic carbon atoms. In yet other embodiments, the alkyl groupcontains 1–4 aliphatic carbon atoms. Examples of alkoxy, include but arenot limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy,tert-butoxy, neopentoxy and n-hexoxy. Examples of thioalkyl include, butare not limited to, methylthio, ethylthio, propylthio, isopropylthio,n-butylthio, and the like.

The term “alkylamino” refers to a group having the structure —NHR′wherein R′ is alkyl, as defined herein. The term “aminoalkyl” refers toa group having the structure NH₂R′—, wherein R′ is alkyl, as definedherein. In certain embodiments, the alkyl group contains 1–20 aliphaticcarbon atoms. In certain other embodiments, the alkyl group contains1–10 aliphatic carbon atoms. In yet other embodiments, the alkyl,alkenyl, and alkynyl groups employed in the invention contain 1–8aliphatic carbon atoms. In still other embodiments, the alkyl groupcontains 1–6 aliphatic carbon atoms. In yet other embodiments, the alkylgroup contains 1–4 aliphatic carbon atoms. Examples of alkylaminoinclude, but are not limited to, methylamino, ethylamino,iso-propylamino and the like.

Some examples of sutstituents of the above-described aliphatic (andother) moieties of compounds of the invention include, but are notlimited to aliphatic; alicyclic; heteroaliphatic; heteroalicyclic; aryl;heteroaryl; alkylaryl; alkylheteroaryl; alkoxy; aryloxy; heteroalkoxy;heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; F;Cl; Br; I; —OH; —NO₂; —CN; —CF₃; —CH₂CF₃; —CH1₂; —CH₂OH; —CH₂CH₂OH;—CH₂NH₂; —CH₂SO₂CH₃; —C(O)R_(x); —CO₂(R_(x)); —CON(R_(x))₂; —OC(O)R_(x);—OCO₂R_(x); —OCON(R_(x))₂; —N(R_(x))₂; —S(O)₂R_(x); —NR_(x)(CO)R_(x)wherein each occurrence of R_(x) independently includes, but is notlimited to, aliphatic, alicyclic, heteroaliphatic, heteroalicyclic,aryl, heteroaryl, alkylaryl, or alkylheteroaryl, wherein any of thealiphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl,heteroaryl, alkylaryl, or alkylheteroaryl, substituents described aboveand herein may be substituted or unsubstituted, branched or unbranched,cyclic or acyclic, and wherein any of the aryl or heteroarylsubstituents described above and herein may be substituted orunsubstituted. Additional examples of generally applicable substituentsare illustrated by the specific embodiments shown in the Examples thatare described herein.

In general, the terms “aryl” and “heteroaryl”, as used herein, refer tostable mono- or polycyclic, heterocyclic, polycyclic, andpolyheterocyclic unsaturated moieties having preferably 3–14 carbonatoms, each of which may be substituted or unsubstituted. It will alsobe appreciated that aryl and heteroaryl moieties, as defined herein maybe attached via an aliphatic, alicyclic, heteroaliphatic,heteroalicyclic, alkyl or heteroalkyl moiety and thus also include-(aliphatic)aryl, -(heteroaliphatic)aryl, -(aliphatic)heteroaryl,-(heteroaliphatic)heteroaryl, -(alkyl)aryl, -(heteroalkyl)aryl,-(heteroalkyl)aryl, and -(heteroalkyl)heteroaryl moieties. Thus, as usedherein, the phrases “aryl or heteroaryl” and “aryl, heteroaryl,-(aliphatic)aryl, -(heteroaliphatic)aryl, -(aliphatic)heteroaryl,-(heteroaliphatic)heteroaryl, -(alkyl)aryl, -(heteroalkyl)aryl,-(heteroalkyl)aryl, and heteroalkyl)heteroaryl” are interchangeable.Substituents include, but are not limited to, any of the previouslymentioned substitutents, i.e., the substituents recited for aliphaticmoieties, or for other moieties as disclosed herein, resulting in theformation of a stable compound. In certain embodiments of the presentinvention, “aryl” refers to a mono- or bicyclic carbocyclic ring systemhaving one or two aromatic rings including, but not limited to, phenyl,naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like. In certainembodiements of the present invention, the term “heteroaryl”, as usedherein, refers to a cyclic aromatic radical having from five to ten ringatoms of which one ring atom is selected from S, O and N; zero, one ortwo ring atoms are additional heteroatoms independently selected from S,O and N; and the remaining ring atoms are carbon, the radical beingjoined to the rest of the molecule via any of the ring atoms, such as,for example, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl,imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl,thiophenyl, furanyl, quilnolinyl, isoquinolinyl, and the like.

It will be appreciated that aryl and heteroaryl groups (includingbycyclic aryl groups) can be unsubstituted or substituted, whereinsubstitution includes replacement of one, two or three of the hydrogenatoms thereon independently with any one or more of the followingmoieties including, but not limited to: aliphatic; alicyclic;heteroaliphatic; heteroalicyclic; aryl; heteroaryl; alkylaryl;alkylheteroaryl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy;alkylthio; arylthio; heteroalkylthio; heteroarylthio; F; Cl; Br; I; —OH;—NO₂; —CN; —CF₃; —CH₂CF₃; —CHCl₂; —CH₂OH; —CH₂CH₂OH; —CH₂NH₂;—CH₂SO₂CH₃; —C(O)R_(x); —CO₂(R_(x)); —CON(R)₂; —OC(O)R_(x); —OCO₂R_(x);—OCON(R_(x))₂; —N(R_(x))₂; —S(O)₂R_(x); —NR_(x)(CO)R_(x) wherein eachoccurrence of R_(x) independently includes, but is not limited to,aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl,heteroaryl, alkylaryl, or alkylheteroaryl, wherein any of the aliphatic,alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl,alkylaryl, or alkylheteroaryl, substituents described above and hereinmay be substituted or unsubstituted, branched or unbranched, cyclic oracyclic, and wherein any of the aryl or heteroaryl substituentsdescribed above and herein may be substituted or unsubstituted.Additional examples of generally applicable substituents are illustratedby the specific embodiments shown in the Examples that are describedherein.

The term “cycloalkyl”, as used herein, refers specifically to groupshaving three to seven, preferably three to ten carbon atoms. Suitablecycloalkyls include, but are not limited to cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl and the like, which, as in the caseof other aliphatic, heteroaliphatic or hetercyclic moieties, mayoptionally be substituted with substituents including, but not limitedto aliphatic; alicyclic; heteroaliphatic; heteroalicyclic; aryl;heteroaryl; alkylaryl; alkyheteroaryl; alkoxy; aryloxy; heteroalkoxy;heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; F;Cl; Br; I; —OH; —NO₂; —CN; —CF₃; —CH₂CF₃; —CHCl₂; —CH₂OH; —CH₂CH₂OH;—CH₂NH₂; —CH₂SO₂CH₃; —C(O)R_(x); —CO₂(R_(x)); —CON(R_(x))₂; —OC(O)R_(x);—OCO₂R_(x); —OCON(R_(x))₂; —N(R_(x))₂; —S(O)₂R_(x); —NR_(x)(CO)R_(x)wherein each occurrence of R_(x) independently includes, but is notlimited to, aliphatic, alicyclic, heteroaliphatic, heteroalicyclic,aryl, heteroaryl, alkylaryl, or alkylheteroaryl, wherein any of thealiphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl,heteroaryl, alkylaryl, or alkylheteroaryl, substituents described aboveand herein may be substituted or unsubstituted, branched or unbranched,cyclic or acyclic, and wherein any of the aryl or heteroarylsubstituents described above and herein may be substituted orunsubstituted. Additional examples of generally applicable substituentsare illustrated by the specific embodiments shown in the Examples thatare described herein.

The term “heteroaliphatic”, as used herein, refers to aliphatic moietiesin which one or more carbon atoms in the main chain have havesubstituted with an heteroatom. Thus, a heteroaliphatic group refers toan aliphatic chain which contains one or more oxygen sulfur, nitrogen,phosphorus or silicon atoms, e.g., in place of carbon atoms.Heteroaliphatic moieties may be branched or linear unbranched. Incertain embodiments, heteroaliphatic moieties are substituted byindependent replacement of one or more of the hydrogen atoms thereonwith one or more moieties including, but not limited to aliphatic;alicyclic; heteroaliphatic; heteroalicyclic; aryl; heteroaryl;alkylaryl; alkylheteroaryl; alkoxy; aryloxy; heteroalkoxy;heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; F;Cl; Br; I; —OH; —NO₂; —CN; —CF₃; —CH₂CF₃; —CHCl₂; —CH₂OH; —CH₂CH₂OH;—CH₂NH₂; —CH₂SO₂CH₃; —C(O)R_(x); —CO₂(R_(x)); —CON(R_(x))₂; —OC(O)R_(x);—OCO₂R_(x); —OCON(R_(x))₂; —N(R_(x))₂; —S(O)₂R_(x); —NR_(x)(CO)R_(x)wherein each occurrence of R_(x) independently includes, but is notlimited to, aliphatic, alicyclic, heteroaliphatic, heteroalicyclic,aryl, heteroaryl, alkylaryl, or alkylheteroaryl, wherein any of thealiphatic, alicyclic, heteroaliphatic, heteroalicyclic, alkylaryl, oralkylheteroaryl substituents described above and herein may besubstituted or unsubstituted, branched or unbranched, cyclic or acyclic,and wherein any of the aryl or heteroaryl substituents described aboveand herein may be substituted or unsubstituted. Additional examples ofgenerally applicable substituents are illustrated by the specificembodiments shown in the Examples that are described herein.

The term “heteroalicyclic”, as used herein, refers to compounds whichcombine the properties of heteroaliphatic and cyclic compounds andinclude but are not limited to saturated and unsaturated mono- orpolycyclic heterocycles such as morpholino, pyrrolidinyl, furanyl,thiofuranyl, pyrrolyl etc., which are optionally substituted with one ormore functional groups.

The terms “halo” and “halogen” as used herein refer to an atom selectedfrom fluorine, chlorine, bromine and iodine.

The term “haloalkyl” denotes an alkyl group, as defined above, havingone, two, or three halogen atoms attached thereto and is exemplified bysuch groups as chloromethyl, bromoethyl, trifluoromethyl, and the like.

The term “heterocycloalkyl” or “heterocycle”, as used herein, refers toa non-aromatic 5-, 6- or 7-membered ring or a polycyclic group,including, but not limited to a bi- or tri-cyclic group comprising fusedsix-membered rings having between one and three heteroatomsindependently selected from oxygen, sulfur and nitrogen, wherein (i)each 5-membered ring has 0 to 1 double bonds and each 6-membered ringhas 0 to 2 double bonds, (ii) the nitrogen and sulfur heteroatoms may beoptionally be oxidized, (iii) the nitrogen heteroatom may optionally bequaternized, and (iv) any of the above heterocyclic rings may be fusedto an aryl or heteroaryl ring. Representative heterocycles include, butare not limited to, pyrrolidinyl, pyrazolinyl, pyrazolidinyl,imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl,isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, andtetrahydrofuryl. In certain embodiments, a “substituted heterocycloalkylor heterocycle” group is utilized and as used herein, refers to aheterocycloalkyl or heterocycle group, as defined above, substituted bythe independent replacement of one, two or three of the hydrogen atomsthereon with but are not limited to aliphatic; alicyclic;heteroaliphatic; heteroalicyclic; aryl; heteroaryl; alkylaryl;alkylheteroaryl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy;alkylthio; arylthio; heteroalkylthio; heteroarylthio; F; Cl; Br; I; —OH;—NO₂; —CN; —CF₃; —CH₂CF₃; —CHCl₂; —CH₂OH; —CH₂CH₂OH; —CH₂NH₂;—CH₂SO₂CH₃; —C(O)R; —CO₂(R_(x)); —CON(R_(x))₂; —OC(O)R_(x); —OCO₂R_(x);—OCON(R_(x))₂; —N(R_(x))₂; —S(O)₂R_(x); —NR_(x)(CO)R_(x) wherein eachoccurrence of R_(x) independently includes, but is not limited to,aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl,heteroaryl, alkylaryl, or alkylheteroaryl, wherein any of the aliphatic,alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl,alkylaryl, or alkylheteroaryl, substituents described above and hereinmay be substituted or unsubstituted, branched or unbranched, cyclic oracyclic, and wherein any of the aryl or heteroaryl substitutentsdescribed above and herein may be substituted or unsubstituted.Additional examples or generally applicable substituents are illustratedby the specific embodiments shown in the Examples, which are describedherein.

As used herein, the terms “aliphatic”, “heteroaliphatic”, “alkyl”,“alkenyl”, “alkynyl”, “heteroalkyl”, “heteroalkenyl”, “heteroalkynyl”,and the like encompass substituted and unsubstituted, saturated andunsaturated, and linear and branched groups. Similarly, the terms“alicyclic”, “heteroalicyclic”, “heterocycloalkyl”, “heterocycle”, andthe like encompass substituted and unsubstituted, and saturated andunsaturated groups. In addition, the terms “aliphatic(aryl)”,“heteroaliphatic(aryl)”, “aliphatic(heteroaryl)”,“heteroaliphatic(heteroaryl)”, “alicyclic(aryl)”,“heteroalicyclic(aryl)”, “alicyclic(heteroaryl)”,“heteroalicyclic(heteroaryl)”, “-alkyl(aryl)”, “heteroalkyl(aryl)”,“-alkyl(heteroaryl)”, “heteroalkyl(heteroaryl)”, and the like encompasssubstituted and unsubstituted, and saturated and unsaturated (i.e.,non-aromatic portion of the moiety) groups. Additionally, the terms“cycloalkyl”, “cycloalkenyl”, “cycloalkynyl”, “heterocycloalkyl”,“heterocycloalkenyl”, “heterocycloalkynyl”, “aryl”, “heteroaryl” and thelike encompass both substituted and unsubstituted groups, unlessotherwise indicated.

3) Synthetic Methodology

According to the present invention, any available techniques can be usedto make or prepare the inventive compounds or compositions includingthem. For example, a variety of solution phase synthetic methods such asthose discussed in detail below may be used. Alternatively oradditionally, the inventive compounds may be prepared using any of avariety combinatorial techniques, parallel synthesis and/or solid phasesynthetic methods known in the art.

In one aspect, the present invention provides novel peptides havingformula (I) as described above and in certain classes and subclassesherein. Examples of synthetic methods for preparing exemplary types ofcompounds of the invention are provided below, as detailed in Schemes1–12, and in the Exemplification herein. It will be appreciated that themethods as described herein can be applied to each of the compounds asdisclosed herein and equivalents thereof. Additionally, the reagents andstarting materials are well known to those skilled in the art. Althoughthe following schemes describe certain exemplary compounds, it will beappreciated that the use of alternate starting materials will yieldother analogs of the invention. For example, compounds are describedbelow where X₁ and X₂ are each C═O, R₅ is hydrogen, R₆ is tert-butyl andR₇ is methyl; however, it will be appreciated that alternate startingmaterials and/or intermediates can be utilized to generate compoundswhere, for example, X₁ and X₂ may be independently C═O, CH₂, SO₂, andR₅–R₇ may represent moieties other than those depicted herein, such asalkyl, heteroalkyl, aryl, heteroaryl, etc. It will also be appreciatedthat any available techniques known in the art can be used to make theinventive compounds or compositions including them. A person of ordinaryskill in the art will recognize that suitable synthetic methods are notlimited to those depicted in Schemes 1–12 below, and that any suitablesynthetic methods known in the art can be used to prepare the inventivecompounds.

In certain embodiments, the inventive compounds, have the generalstructure (I′) as shown in Scheme 1, where R, R′ and Q are aliphatic,heteroaliphatic, aryl or heteroaryl moieties. In preferred embodiments,R, R′ and Q are moieties such as those described in classes andsubclasses herein. Examples of preferred structures for R, R′ and Q aredepicted in Scheme 1.

In certain embodiments, the inventive compounds belong to class (Ia) andsubclasses thereof, as described herein. Scheme 2 depicts the synthesisof exemplary compounds of this class (compounds of general structure11). As shown in Scheme 2, the dipeptide core can be constructed, forexample, from N-Boc-N-methyl-valinal (2) and N-Boc-tert-leucine (4). TheN-terminal moiety of the compounds of the invention (R′ in Scheme 1) maybe provided by (S)—N-Boc-neo-phenylalanine (6). As depicted in Scheme 2,a variety of synthetic methods allow access to a variety of analogs, forexample, carboxylic esters of general structure 7, carboxylic acid 8 oramides of general structure 11. The reader will appreciate that othersynthetic methods known in the art can be used to prepare otherderivatives.

An exemplary synthetic approach for the preparation of intermediate 6 isdepicted in Scheme 3. The method afforded (S)-N-Boc-neo-phenylalanine(6) in 20% overall yield.

In certain other embodiments, the inventive compounds belong to class(Ib) and subclasses thereof, as described herein. Schemes 4–6 depict thesynthesis of exemplary types of compounds of this class (for example,Amine Esters, Amine Acids, Amine Amides and N-Acetyl Amine Amides ofgeneral structure 18, 20, 23, respectively as seen in Schemes 4; Seealso Amine Esters, Amine Acids, Amine Amides and N-Acetyl Amine Amidesof general structure 25, 26 and 27, respectively in Scheme 5). Incertain embodiments, R may be a nitrogen-containing heteroalkyl moiety(see Schemes 4 and 5) or an unsaturated oxygen-containing heteroalkylmoiety (see Scheme 6). Although Schemes 4–6 depict compounds comprisingan N-terminal moiety derived from (S)-N-Boc-neo-phenylalanine (6), aperson of ordinary skill in the art would appreciate that a wide varietyof organic moieties other than those described in Schemes 4–6 may beused to construct the compounds of the invention. Similarly, Schemes 4–6recite compounds where the C-terminal moiety may be carboxylic esters,carboxylic acids or amides. It is to be understood that the scope of theinvention is not limited to these compounds, but rather encompassesderivatives and analogs of these compounds, or compounds obtained fromdifferent starting materials.

In certain other embodiments, the inventive compounds belong to class(Ic) and subclasses thereof, as described herein. Schemes 7–10 depictthe synthesis of exemplary types of compounds of this class (for exampleAmine Esters, Amine Acids and Amine Amides of general structure 42, 43and 45, respectively, as seen in Scheme 7). In certain embodiments, thecompounds of the invention comprise a nitrogen-containing heterocyclicN-terminal moiety. For example, the heterocyclic moiety may be apiperidine ring (Schemes 7, 8 and 9) or a thiazolidine ring (Scheme 10).Examples of other suitable moieties are described in the Examplificationherein, or will be apparent to the person of ordinary skill in the art.As discussed above, R may be a nitrogen-containing heteroalkyl moiety(Scheme 7) or an unsaturated alkyl moiety (Schemes 8, 9 and 10).

Methylpipecolic Acid Analogs

In certain other embodiments, the inventive compounds belong to class(Id) and subclasses thereof, as described herein. One skilled in the artwould appreciate that the exemplary heterocyclic starting materialsdescribed in Schemes 7–10, that are used in the preparation of compoundsof class (Ic) (namely compounds 38, 60 or 65) could be substituted foracyclic α-amino acid moieties to access compounds of class (Id), asillustrated in Scheme 11 below:

For example, reaction of diethylglycine (72) with amine HCl salt 49gives the N-terminal gem-diethyl ethyl ester 73, or the correspondingcarboxylic acid 74, after hydrolysis under suitable conditions (Scheme12).

It will be appreciated that each of the reactions described in Schemes2–12 above can be carried out using reagents and conditions as describedfor the synthesis of various types of exemplary compounds describedabove, or they may be modified using other available reagents orstarting materials. For example, a variety of amide formationconditions, esterification, hydrolysis and aromatic nucleusfunctionalization conditions are well-known in the art and can beutilized in the method of the invention. See generally, March, AdvancedOrganic Chemistry, 5^(th) ed., John Wiley & Sons, 2001; and“Comprehensive Organic Transformations, a guide to functional grouppreparations”, Richard C. Larock, VCH publishers, 1999; the entirecontents of which are incorporated herein by reference.

As mentioned above, it will be appreciated that the invention is notlimited in scope to the compounds recited herein. Synthetic strategiesor starting materials other than those described herein may be used toprepare compounds of general structure (I). It will also be appreciatedthat each of the components/starting materials used in the synthesis ofthe compounds of the invention can be diversified either beforesynthesis or alternatively after the construction of the peptideconstruct. As used herein, the term “diversifying” or “diversify” meansreacting an inventive compound, as defined herein, at one or morereactive sites to modify a functional moiety or to add a functionalmoiety. For example, where an aromatic ring is present in the compound,the aromatic ring can be diversified (prior to or after reaction) toeither add functionality (e.g., where hydrogen is present, a halogen orother functionality can be added) or to modify functionality (e.g.,where a hydroxyl group is present on the aromatic ring, the aromaticring can be diversified by reacting with a reagent to protect thehydroxyl group, or to convert it into an aliphatic or heteroaliphaticmoiety). Described generally below are a variety of schemes to assistthe reader in the synthesis of a variety of analogues, either bydiversification of the intermediate components or by diversification ofthe peptide construct.

In certain embodiments, the preparation of chemically diversederivatives may be achieved by diversifying the C-terminal moiety of thecompounds. For example, where the C-terminal moiety is a carboxylicacid, examples of chemical transformations suitable to achieve suchderivatization include, but are not limited to, reduction to thecorresponding aldehyde or alcohol, amidation, Wittig reaction,decarboxylation, esterification, addition of nucleophiles, conversion toketones, imines, hydrazones, azides, etc . . . Examples of suchtransformations are depicted in Schemes 12 and 13. One skilled in theart will recognize that possible chemical transformations suitable toachieve diversification of the compounds of the invention are notlimited to those depicted in Schemes 1–13. Rather, any suitablesynthetic methods known in the art can be used to achieve desiredchemical transformations.

4) Research Uses, Formulation and Administration

According to the present invention, the inventive compounds may beassayed in any of the available assays known in the art for identifyingcompounds having a pre-determined biological activity. For example, theassay may be cellular or non-cellular, in vivo or in vitro, high- orlow-throughput format, etc. In certain exemplary embodiments, theinventive compounds are tested in assays to identify those compoundshaving cytotoxic or growth inhibitory effect in vitro, or cause tumorregression and/or inhibition of tumor growth in vivo.

Compounds of this invention which are of particular interest includethose which:

-   -   exhibit cytotoxic and/or growth inhibitory effect on cancer cell        lines maintained in vitro or in animal studies using a        scientifically acceptable cancer cell xenograft model;    -   preferably cause tumor regression in vivo;    -   exhibit low sensitivity to MDR;    -   exhibit low cytotoxicity to non-dividing normal cells; and/or    -   exhibit a favorable therapeutic profile (e.g., safety, efficacy,        and stability).

As detailed in the exemplification herein, in assays to determine theability of compounds to inhibit the growth of tumor cell lines in vitro,certain inventive compounds exhibited IC₅₀ values 10 μM. In otherembodiments, compounds of the invention exhibit IC₅₀ values 5 μM. Inother embodiments, compounds of the invention exhibit IC₅₀ values 1 μM.In other embodiments, compounds of the invention exhibit IC₅₀ values 750nM. In other embodiments, compounds of the invention exhibit IC₅₀ values500 nM. In other embodiments, compounds of the invention exhibit IC₅₀values 250 nM. In other embodiments, compounds of the invention exhibitIC₅₀ values 100 nM. In other embodiments, compounds of the inventionexhibit IC₅₀ values 50 nM. In other embodiments, compounds of theinvention exhibit IC₅₀ values 25 nM. In other embodiments, compounds ofthe invention exhibit IC₅₀ values 10 nM. In other embodiments, compoundsof the invention exhibit IC₅₀ values 7.5 nM. In other embodiments,compounds of the invention exhibit IC₅₀ values 5 nM. In otherembodiments, compounds of the invention exhibit IC₅₀ values 2.5 nM. Inother embodiments, compounds of the invention exhibit IC₅₀ values 1 nM.In other embodiments, compounds of the invention exhibit IC₅₀ values0.75 nM. In other embodiments, compounds of the invention exhibit IC₅₀values 0.5 nM. In other embodiments, compounds of the invention exhibitIC₅₀ values 0.25 nM. In other embodiments, compounds of the inventionexhibit IC₅₀ values 0.1 nM. In certain embodiments, compounds of theinvention exhibit growth inhibition IC₅₀ values in cultured human cancercells in the range of 0.1 nM–10 nM.

In certain other embodiments, compounds of the invention exhibit lowsensitivity to MDR. In certain exemplary embodiments, compounds of theinvention have a ratio [cell growth inhibition in MDR-positivecells]/[cell growth inhibition in MDR-negative cells] (i.e., resistanceratio) 10. In certain exemplary embodiments, compounds of the inventionhave a resistance ratio 9. In certain exemplary embodiments, compoundsof the invention have a resistance ratio 8. In certain exemplaryembodiments, compounds of the invention have a resistance ratio 7. Incertain exemplary embodiments, compounds of the invention have aresistance ratio 6. In certain exemplary embodiments, compounds of theinvention have a resistance ratio 5. In certain exemplary embodiments,compounds of the invention have a resistance ratio 4.

In certain other embodiments, compounds of the invention exhibit lowcytotoxicity to non-dividing normal cells. In certain exemplaryembodiments, inventive compounds exhibit little or no cytotoxicity innon-dividing normal cells at concentrations 1000 fold the concentrationat which they inhibit cancer cell growth. In certain exemplaryembodiments, inventive compounds exhibit little or no cytotoxicity innon-dividing normal cells at concentrations in the range of up to 1–10μM.

In certain embodiments, inventive compounds exhibit stability in mouseserum.

In certain embodiments, inventive compounds exhibit a low mitotic blockreversibility ratio. In certain embodiments, inventive compounds exhibitmitotic block reversibility ratios of 1 to about 30. In certainembodiments, inventive compounds exhibit mitotic block reversibilityratios of 1 to about 25. In certain embodiments, inventive compoundsexhibit mitotic block reversibility ratios of 1 to about 20. In certainembodiments, inventive compounds exhibit mitotic block reversibilityratios of 1 to about 15. In certain embodiments, inventive compoundsexhibit mitotic block reversibility ratios of 1 to about 10. In certainembodiments, inventive compounds exhibit mitotic block reversibilityratios of 1 to about 5. In certain embodiments, inventive compoundsexhibit mitotic block reversibility ratios of 1 to about 3.

In certain embodiments, compounds of the invention cause tumorregression in vivo. In certain exemplary embodiments, compounds of theinvention cause tumor regression in vivo in suitable mouse tumorxenograph models. In certain exemplary embodiments, compounds of theinvention cause reduction of tumor size to below 70% of the size at thestart of compound administration in a suitable cancer cell xenograftmodel. In certain exemplary embodiments, compounds of the inventioncause reduction of tumor size to below 65% of the size at the start ofcompound administration in a suitable cancer cell xenograft model. Incertain exemplary embodiments, compounds of the invention causereduction of tumor size to below 60% of the size at the start ofcompound administration in a suitable cancer cell xenograft model. Incertain exemplary embodiments, compounds of the invention causereduction of tumor size to below 55% of the size at the start ofcompound administration in a suitable cancer cell xenograft model. Incertain exemplary embodiments, compounds of the invention causereduction of tumor size to below 50% of the size at the start ofcompound administration in a suitable cancer cell xenograft model. Incertain exemplary embodiments, compounds of the invention cause tumorregression in certain multidrug resistant xenograph models.

In certain exemplary embodiments, compounds of the invention causeinhibition of tumor growth in vivo. In certain exemplary embodiments,compounds of the invention cause significant inhibition of tumor growthin suitable cancer cell xenograft models. In certain exemplaryembodiments, compounds of the invention cause significant inhibition oftumor growth in suitable multidrug resistant cancer cell xenograftmodels. In certain exemplary embodiments, compounds of the inventioncause inhibition of tumor growth in treated animals by >50% compared tothat of control aninals (i.e., “treated” tumor size <50% “control” tumorsize; or T/C value <50%) in suitable cancer cell xenograft models. Incertain embodiments, compounds of the invention have T/C values <70%. Incertain embodiments, compounds of the invention have T/C values <65%. Incertain embodiments, compounds of the invention have T/C values <60%. Incertain embodiments, compounds of the invention have T/C values <55%.

In certain embodiments, compounds of the invention inhibit the growth ofhuman cancer cells in vitro, exhibit low sensitivity to MDR (e.g., lowresistance ratio), exhibit low cytotoxicity to non-dividing normalcells, exhibit stability in mouse serum, have a low mitotic blockreversibility ratio, cause tumor regression in vivo, and/or causeinhibition of tumor growth in vivo.

In certain embodiments, compounds of the invention inhibit the growth ofhuman cancer cells in vitro, exhibit low sensitivity to MDR (e.g., lowresistance ratio), exhibit low cytotoxicity to non-dividing normalcells, exhibit stability in mouse serum, have a low mitotic blockreversibility ratio, cause tumor regression in vivo, and causeinhibition of tumor growth in vivo.

In certain embodiments, compounds of the invention have any one or moreof the following properties:

-   (i) exhibit growth inhibition IC₅₀ values in cultured human cancer    cells in the range of 0.1 nM–10 nM;-   (ii) have a resistance ratio preferably 10, preferably 9, preferably    S, preferably 7, preferably 6, preferably 5, more preferably 4;-   (iii) exhibit little or no cytotoxicity in non-dividing normal cells    at concentrations in the range of up to 1–10 μM;-   (iv) exhibit stability in mouse serum;-   (v) exhibit mitotic block reversibility ratios of 1 to about 30,    preferably of 1 to about 25, preferably of 1 to about 20, preferably    of 1 to about 15, preferably of 1 to about 10, preferably of 1 to    about 5, most preferably of about 1 to about 3;-   (vi) cause reduction of tumor size to below 70%, preferably below    65%, preferably below 60%, preferably below 55%, most preferably    below 50%, of the size at the start of compound administration in    suitable cancer cell xenograft models; and/or-   (vii) cause significant inhibition of tumor growth in suitable    cancer cell xenograft model (e.g., T/C value preferably <70%,    preferably <65%, preferably <60%, preferably <55%, most preferably    <50%).

In certain embodiments, compounds of the invention have the followingproperties:

-   (i) exhibit growth inhibition IC₅₀ values in cultured human cancer    cells in the range of 0.1 nM–10 nM;-   (ii) have a resistance ratio preferably 10, preferably 9, preferably    8, preferably 7, preferably 6, preferably 5, more preferably 4;-   (iii) exhibit little or no cytotoxicity in non-dividing normal cells    at concentrations in the range of up to 1–10 μM;-   (iv) exhibit stability in mouse serum;-   (v) exhibit mitotic block reversibility ratios of 1 to about 30,    preferably of 1 to about 25, preferably of 1 to about 20, preferably    of 1 to about 15, preferably of 1 to about 10, preferably of 1 to    about 5, most preferably of about 1 to about 3;-   (vi) cause reduction of tumor size to below 70%, preferably below    65%, preferably below 60%, preferably below 55%, most preferably    below 50%, of the size at the start of compound administration in    suitable cancer cell xenograft models; and-   (vii) cause significant inhibition of tumor growth in suitable    cancer cell xenograft model (e.g., T/C value preferably <70%,    preferably <65%, preferably <60%, preferably <55%, most preferably    <50%).

Examples of compounds exhibiting desired properties include ER-805913,ER-805736, ER-807102, ER-807328, ER-806925, ER-807850, ER-807904,ER-807974, ER-808368, ER-808662, ER-808824, and salts thereof (See Tablebelow).

As discussed above, compounds of the invention exhibit activity for theinhibition of tumor cell growth. As such, the inventive compounds asuseful for the treatment of a variety of disorders, including, but notlimited to, glioblastoma, retinoblastoma, breast cancer, cervicalcancer, colon and rectal cancer, leukemia, lung cancer (including, butnot limited to small cell lung cancer), melanoma, multiple myeloma,non-Hodgkin's lymphoma, ovarian cancer, pancreatic cancer, prostatecancer and gastric cancer, to name a few. In certain embodiments, theinventive compounds are useful for the treatment of solid and non-solidtumors. In still other embodiments of interest, the inventive compoundsare particularly useful for the treatment of breast cancer, prostatecancer, colon cancer, lung cancer, leukemia and lymphoma.

In certain embodiment, the method involves the administration of atherapeutically effective amount of the compound or a pharmaceuticallyacceptable derivative thereof to a subject (including, but not limitedto a human or animal) in need of it. In certain embodiments, theinventive compounds as useful for the treatment of cancer (including,but not limited to, glioblastoma, retinoblastoma, breast cancer,cervical cancer, colon and rectal cancer, leukemia, lymphoma, lungcancer (including, but not limited to small cell lung cancer), melanomaand/or skin cancer, multiple myeloma, non-Hodgkin's lymphoma, ovariancancer, pancreatic cancer, prostate cancer and gastric cancer, bladdercancer, uterine cancer, kidney cancer, testicular cancer, stomachcancer, brain cancer, liver cancer, or esophageal cancer).

Pharmaceutical Compositions

As discussed above this invention provides novel compounds that havebiological properties useful for the treatment of cancer. In certainembodiments, certain of the compounds as described herein act asinhibitors of tumor growth and thus are useful in the treatment ofcancer and in the inhibition of tumor growth and in the killing ofcancer cells. In certain embodiments, the inventive compounds are usefulfor the treatment of solid tumors or non-solid tumors. In still otherembodiments of interest, the inventive compounds are useful for thetreatment of glioblastoma, retinoblastoma, breast cancer, cervicalcancer, colon and rectal cancer, leukemia, lymphoma, lung cancer(including, but not limited to small cell lung cancer), melanoma,multiple myeloma, non-Hodgkin's lymphoma, ovarian cancer, pancreaticcancer, prostate cancer and gastric cancer, to name a few. The inventivecompounds also find use in the prevention of restenosis of blood vesselssubject to traumas such as angioplasty and stenting.

Accordingly, in another aspect of the present invention, pharmaceuticalcompositions are provided, which comprise any one of the compoundsdescribed herein (or a prodrug, pharmaceutically acceptable salt orother pharmaceutically acceptable derivative thereof), and optionallycomprise a pharmaceutically acceptable carrier. In certain embodiments,the compounds are capable of inhibiting the growth of or killing cancercells. In certain embodiments, these compositions optionally furthercomprise one or more additional therapeutic agents. Alternatively, acompound of this invention may be administered to a patient in needthereof in combination with the administration of one or more othertherapeutic agents. For example, additional therapeutic agents forconjoint administration or inclusion in a pharmaceutical compositionwith a compound of this invention may be a cytotoxic agent or anticanceragent approved for the treatment of cancer, as discussed in more detailherein, or it may be any one of a number of agents undergoing approvalin the Food and Drug Administration that ultimately obtain approval forthe treatment of an immune disorder or cancer. It will also beappreciated that certain of the compounds of present invention can existin free form for treatment, or where appropriate, as a pharmaceuticallyacceptable derivative thereof. According to the present invention, apharmaceutically acceptable derivative includes, but is not limited to,pharmaceutically acceptable salts, esters, salts of such esters, or aprodrug or other adduct or derivative of a compound of this inventionwhich upon administration to a patient in need is capable of providing,directly or indirectly, a compound as otherwise described herein, or ametabolite or residue thereof.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgement,suitable for use in contact with the tissues of humans and lower animalswith little or no undue toxicity, irritation, allergic response and thelike, and are commensurate with a reasonable benefit/risk ratio.Pharmaceutically acceptable salts of amines, carboxylic acids, and othertypes of compounds, are well known in the art. For example, S. M. Berge,et al. describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 66: 1–19 (1977), incorporated herein byreference. The salts can be prepared in situ during the final isolationand purification of the compounds of the invention, or separately byreacting a free base or free acid function with a suitable reagent, asdescribed generally below. For example, a free base function can bereacted with a suitable acid. Furthermore, where the compounds of theinvention carry an acidic moiety, suitable pharmaceutically acceptablesalts thereof may, include metal salts such as alkali metal salts, e.g.sodium or potassium salts; and alkaline earth metal salts, e.g. calciumor magnesium salts. Examples of pharmaceutically acceptable, nontoxicacid addition salts are salts of an amino group formed with inorganicacids such as hydrochloric acid, hydrobromic acid, phosphoric acid,sulfuric acid and perchloric acid or with organic acids such as aceticacid, oxalic acid, maleic acid, tartaric acid, citric acid, succinicacid or malonic acid or by using other methods used in the art such asion exchange. Other pharmaceutically acceptable salts include adipate,alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate,borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hernisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, trifluoroacetate, undecanoate, valeratesalts, and the like. Representative alkali or alkaline earth metal saltsinclude sodium, lithium, potassium, calcium, magnesium, and the like.Further pharmaceutically acceptable salts include, when appropriate,nontoxic ammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, loweralkyl sulfonate and aryl sulfonate.

Additionally, as used herein, the term “pharmaceutically acceptableester” refers to esters that hydrolyze in vivo and include those thatbreak down readily in the human body to leave the parent compound or asalt thereof. Suitable ester groups include, for example, those derivedfrom pharmaceutically acceptable aliphatic carboxylic acids,particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, inwhich each alkyl or alkenyl moeity advantageously has not more than 6carbon atoms. Examples of particular esters include formates, acetates,propionates, butyrates, acrylates and ethylsuccinates.

Furthermore, the term “pharmaceutically acceptable prodrugs” as usedherein refers to those prodrugs of the compounds of the presentinvention which are, within the scope of sound medical judgment,suitable for use in contact with the issues of humans and lower animalswith undue toxicity, irritation, allergic response, and the like,commensurate with a reasonable benefit/risk ratio, and effective fortheir intended use, as well as the zwitterionic forms, where possible,of the compounds of the invention. The term “prodrug” refers tocompounds that are rapidly transformed in vivo to yield the parentcompound of the above formula, for example by hydrolysis in blood. Athorough discussion is provided in T. Higuchi and V. Stella, Pro-drugsas Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, andin Edward B. Roche, ed., Bioreversible Carriers in Drug Design, AmericanPharmaceutical Association and Pergamon Press, 1987, both of which areincorporated herein by reference.

As described above, the pharmaceutical compositions of the presentinvention additionally comprise a pharmaceutically acceptable carrier,which, as used herein, includes any and all solvents, diluents, or otherliquid vehicle, dispersion or suspension aids, surface active agents,isotonic agents, thickening or emulsifying agents, preservatives, solidbinders, lubricants and the like, as suited to the particular dosageform desired. Remington's Pharmaceutical Sciences, Sixteenth Edition, E.W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses variouscarriers used in formulating pharmaceutical compositions and knowntechniques for the preparation thereof. Except insofar as anyconventional carrier medium is incompatible with the compounds of theinvention, such as by producing any undesirable biological effect orotherwise interacting in a deleterious manner with any othercomponent(s) of the pharmaceutical composition, its use is contemplatedto be within the scope of this invention. Some examples of materialswhich can serve as pharmaceutically acceptable carriers include, but arenot limited to, sugars such as lactose, glucose and sucrose; starchessuch as corn starch and potato starch; cellulose and its derivativessuch as sodium carboxymethyl cellulose, ethyl cellulose and celluloseacetate; powdered tragacanth; malt; gelatine; talc; excipients such ascocoa butter and suppository waxes; oils such as peanut oil, cottonseedoil; safflower oil, sesame oil; olive oil; corn oil and soybean oil;glycols; such as propylene glycol; esters such as ethyl oleate and ethyllaurate; agar; buffering agents such as magnesium hydroxide and aluminumhydroxide; alginic acid; pyrogenfree water; isotonic saline; Ringer'ssolution; ethyl alcohol, and phosphate buffer solutions, as well asother non-toxic compatible lubricants such as sodium lauryl sulfate andmagnesium stearate, as well as coloring agents, releasing agents,coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition,according to the judgment of the formulator.

Uses and Formulations of Compounds of the Invention

As described in more detail herein, in general, the present inventionprovides compounds useful for the treatment of cancer and proliferativedisorders.

As discussed above, certain of the compounds as described herein act asinhibitors of tumor growth and thus are useful in the treatment ofcancer and in the inhibition of tumor growth and in the killing ofcancer cells. The invention further provides a method for inhibitingtumor growth and/or tumor metastasis. The method involves theadministration of a therapeutically effective amount of the compound ora pharmaceutically acceptable derivative thereof to a subject(including, but not limited to a human or animal) in need of it. Incertain embodiments, the inventive compounds are useful for thetreatment of solid tumors or non-solid tumors. In still otherembodiments of interest, the inventive compounds are useful for thetreatment of glioblastoma, retinoblastoma, breast cancer, cervicalcancer, colon and rectal cancer, leukemia, lymphoma, lung cancer(including, but not limited to small cell lung cancer), melanoma,multiple myeloma, non-Hodgkin's lymphoma, ovarian cancer, pancreaticcancer, prostate cancer and gastric cancer, to name a few.

As described in more detail herein, in general, the present inventionprovides compounds useful for the treatment of cancer, particularlysolid and non-solid tumors. Specifically, certain compounds of theinvention have been shown to inhibit the growth of certain tumor celllines in vitro, as described in more detail herein, and are useful forthe treatment of cancer, including solid and non-solid tumors.

As discussed above, the inventive compounds also find use in theprevention of restenosis of blood vessels subject to traumas such asangioplasty and stenting. For example, it is contemplated that thecompounds of the invention will be useful as a coating for implantedmedical devices, such as tubings, shunts, catheters, artificialimplants, pins, electrical implants such as pacemakers, and especiallyfor arterial or venous stents, including balloon-expandable stents. Incertain embodiments inventive compounds may be bound to an implantablemedical device, or alternatively, may be passively adsorbed to thesurface of the implantable device. In certain other embodiments, theinventive compounds may be formulated to be contained within, or,adapted to release by a surgical or medical device or implant, such as,for example, stents, sutures, indwelling catheters, prosthesis, and thelike.

In certain exemplary embodiments, the inventive compounds may be used ascoating for stents. A stent is typically an open tubular structure thathas a pattern (or patterns) of apertures extending from the outersurface of the stent to the lumen. It is commonplace to make stents ofbiocompatible metallic materials, with the patterns cut on the surfacewith a laser machine. The stent can be electro-polished to minimizesurface irregularities since these irregularities can trigger an adversebiological response. However, stents may still stimulate foreign bodyreactions that result in thrombosis or restenosis. To avoid thesecomplications, a variety of stent coatings and compositions have beenproposed in the prior art literature both to reduce the incidence ofthese complications or other complications and restore tissue functionby itself or by delivering therapeutic compound to the lumen. Forexample, drugs having antiproliferative and anti-inflammatory activitieshave been evaluated as stent coatings, and have shown promise inpreventing retenosis (See, for example, Presbitero P. et al., “Drugeluting stents do they make the difference?”, Minerva Cardioangiol,2002, 50(5):431–442; Ruygrok P. N. et al., “Rapamycin in cardiovascularmedicine”, Intern. Med. J., 2003, 33(3):103–109; and Marx S. O. et al.,“Bench to bedside: the development of rapamycin and its application tostent restenosis”, Circulation, 2001, 104(8):S52–855, each of thesereferences is incorporated herein by reference in its entirety).Accordingly, without wishing to be bound to any particular theory,Applicant proposes that the inventive compounds, havingantiproliferative effects, can be used as stent coatings and/or in stentdrug delivery devices, inter alia for the prevention of restenosis. Avariety of compositions and methods related to stent coating and/orlocal stent drug delivery for preventing restenosis are known in the art(see, for example, U.S. Pat. Nos. 6,517,889; 6,273,913; 6,258,121;6,251,136; 6,248,127; 6,231,600; 6,203,551; 6,153,252; 6,071,305;5,891,507; 5,837,313 and published U.S. patent application No.US2001/0027340, each of which is incorporated herein by reference in itsentirety). For example, stents may be coated with polymer-drugconjugates by dipping the stent in polymer-drug solution or spraying thestent with such a solution. In certain embodiment, suitable materialsfor the implantable device include biocompatible and nontoxic materials,and may be chosen from the metals such as nickel-titanium alloys, steel,or biocompatible polymers, hydrogels, polyurethanes, polyethylenes,ethylenevinyl acetate copolymers, etc. In certain embodiments, theinventive compound, is coated onto a stent for insertion into an arteryor vein following balloon angioplasty.

The invention may be described therefore, in certain broad aspects as amethod of inhibiting arterial restenosis or arterial occlusion followingvascular trauma comprising administering to a subject in need thereof, acomposition comprising an inventive compound conjugated to a suitablepolymer or polymeric material. In the practice of the method, thesubject may be a coronary bypass, vascular surgery, organ transplant orcoronary or any other arterial angioplasty patient, for example, and thecomposition may be administered directly, intravenously, or even coatedon a stent to be implanted at the sight of vascular trauma.

In another aspect, the invention encompasses implants and surgical ormedical devices, including stents and grafts, coated with or otherwiseconstructed to contain and/or release any of the inventive compoundsdisclosed herein. In certain embodiments, the compounds haveantiproliferative activity. In certain other embodiments, the compoundsinhibit smooth muscle cell proliferation. Representative examples of theinventive implants and surgical or medical devices includecardiovascular devices (e.g., implantable venous catheters, venousports, tunneled venous catheters, chronic infusion lines or ports,including hepatic artery infusion catheters, pacemaker wires,implantable defibrillators); neurologic/neurosurgical devices (e.g.,ventricular peritoneal shunts, ventricular atrial shunts, nervestimulator devices, dural patches and implants to prevent epiduralfibrosis post-laminectomy, devices for continuous subarachnoidinfusions); gastrointestinal devices (e.g. chronic indwelling catheters,feeding tubes, portosystemic shunts, shunts for ascites, peritonealimplants for drug delivery, peritoneal dialysis catheters, implantablemeshes for hernias, suspensions or solid implants to prevent surgicaladhesions, including meshes); genitourinary devices (e.g., uterineimplants, including intrauterine devices (IUDs) and devices to preventendometrial hyperplasia, fallopian tubal implants, including reversiblesterilization devices, fallopian tubal stents, artificial sphincters andperiurethral implants for incontinence, ureteric stents, chronicindwelling catheters, bladder augmentations, or wraps or splints forvasovasostomy); phthalmonlogic implants (e.g., multino implants andother implants for neovascular glaucoma, drug eluting contact lenses forpterygiums, splints for failed dacrocystalrhinostomy, drug elutingcontact lenses for corneal neovascularity, implants for diabeticretinopathy, drug eluting contact lenses for high risk cornealtransplants); otolaryngology devices (e.g., ossicular implants,Eustachian tube splints or stents for glue ear or chronic otitis as analternative to transtempanic drains); plastic surgery implants (e.g.,prevention of fibrous contracture in response to gel- orsaline-containing breast implants in the subpectoral or subglandularapproaches or post-mastectomy, or chin implants), and orthopedicimplants (e.g., cemented orthopedic prostheses).

Implants and other surgical or medical devices may be coated with (orotherwise adapted to release) compositions of the present invention in avariety of manners, including for example: (a) by directly affixing tothe implant or device an inventive compound or composition (e.g., byeither spraying the implant or device with a polymer/drug film, or bydipping the implant or device into a polymer/drug solution, or by othercovalent or noncovalent means); (b) by coating the implant or devicewith a substance such as a hydrogel which will in turn absorb theinventive compound or composition; (c) by interweaving inventivecompound- or composition-coated thread (or the polymer itself formedinto a thread) into the implant or device; (d) by inserting the implantor device into a sleeve or mesh which is comprised of or coated with aninventive compound or composition; (e) constructing the implant ordevice itself with an inventive compound or composition; or (f) byotherwise adapting the implant or device to release the inventivecompound. In certain embodiments, the composition should firmly adhereto the implant or device during storage and at the time of insertion.The inventive compound or composition should also preferably not degradeduring storage, prior to insertion, or when warmed to body temperatureafter insertion inside the body (if this is required). In addition, itshould preferably coat the implant or device smoothly and evenly, with auniform distribution of inventive compound, while not changing the stentcontour. Within preferred embodiments of the invention, the inventiveimplant or device should provide a uniform, predictable, prolongedrelease of the inventive compound or composition into the tissuesurrounding the implant or device once it has been deployed. Forvascular stents, in addition to the above properties, the compositionshould not render the stent thrombogenic (causing blood clots to form),or cause significant turbulence in blood flow (more than the stentitself would be expected to cause if it was uncoated).

In the case of stents, a wide variety of stents may be developed tocontain and/or release the inventive compounds or compositions providedherein, including esophageal stents, gastrointestinal stents, vascularstents, biliary stents, colonic stents, pancreatic stents, ureteric andurethral stents, lacrimal stents, Eustachian tube stents, fallopian tubestents and tracheal/bronchial stents (See, for example, U.S. Pat. No.6,515,016, the entire contents of which are incorporated herein byreference). Stents may be readily obtained from commercial sources, orconstructed in accordance with well-known techniques. Representativeexamples of stents include those described in U.S. Pat. No. 4,768,523,entitled “Hydrogel Adhesive”; U.S. Pat. No. 4,776,337, entitled“Expandable Intraluminal Graft, and Method and Apparatus for Implantingand Expandable Intraluminal Graft”; U.S. Pat. No. 5,041,126 entitled“Endovascular Stent and Delivery System”; U.S. Pat. No. 5,052,998entitled “Indwelling Stent and Method of Use”; U.S. Pat. No. 5,064,435entitled “Self-Expanding Prosthesis Having Stable Axial Length”; U.S.Pat. No. 5,089,606, entitled “Water-insoluble Polysaccharide HydrogelFoam for Medical Applications”; U.S. Pat. No. 5,147,370, entitled“Nitinol Stent for Hollow Body Conduits”; U.S. Pat. No. 5,176,626,entitled “Indwelling Stent”; U.S. Pat. No. 5,213,580, entitled“Biodegradable Polymeric Endoluminal Sealing Process”; and U.S. Pat. No.5,328,471, entitled “Method and Apparatus for Treatment of Focal Diseasein Hollow Tubular Organs and Other Tissue Lumens.”

As discussed above, the stent coated with (or otherwise adapted torelease) compositions of the present invention may be used to eliminatea vascular obstruction and prevent restenosis and/or reduce the rate ofrestenosis. Within other aspects of the present invention, stents coatedwith (or otherwise adapted to release) compositions of the presentinvention are provided for expanding the lumen of a body passageway.Specifically, a stent having a generally tubular structure, and asurface coated with (or otherwise adapted to release) an inventivecompound or composition may be inserted into the passageway, such thatthe passageway is expanded. In certain embodiments, the stent coatedwith (or otherwise adapted to release) compositions of the presentinvention may be used to eliminate a biliary, gastrointestinal,esophageal, tracheal/bronchial, urethral or vascular obstruction.

In another aspect of the invention, methods for the treatment of cancerare provided comprising administering a therapeutically effective amountof a compound of formula (I), as described herein, to a subject in needthereof. In certain embodiments, the inventive compounds are useful forthe treatment of solid and non-solid tumors. It will be appreciated thatthe compounds and compositions, according to the method of the presentinvention, may be administered using any amount and any route ofadministration effective for the treatment of cancer. Thus, theexpression “effective amount” as used herein, refers to a sufficientamount of agent to kill or inhibit the growth of tumor cells, or refersto a sufficient amount to reduce the growth of tumor cells. The exactamount required will vary from subject to subject, depending on thespecies, age, and general condition of the subject, the severity of theinfection, the particular anticancer agent, its mode of administration,and the like. The compounds of the invention are preferably formulatedin dosage unit form for ease of administration and uniformity of dosage.The expression “dosage unit form” as used herein refers to a physicallydiscrete unit of therapeutic agent appropriate for the patient to betreated. It will be understood, however, that the total daily usage ofthe compounds and compositions of the present invention will be decidedby the attending physician within the scope of sound medical judgment.The specific therapeutically effective dose level for any particularpatient or organism will depend upon a variety of factors including thedisorder being treated and the severity of the disorder; the activity ofthe specific compound employed; the specific composition employed; theage, body weight, general health, sex and diet of the patient; the timeof administration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed; andlike factors well known in the medical arts (see, for example, Goodmanand Gilman's, “The Pharmacological Basis of Therapeutics”, TenthEdition, A. Gilman, J. Hardman and L. Limbird, eds., McGraw-Hill Press,155–173, 2001, which is incorporated herein by reference in itsentirety).

In certain other embodiments, methods are provided for using theinventive implants and other surgical or medical devices coated with (orotherwise adapted to release) compounds and compositions of the presentinvention. In certain embodiments, methods are provided for preventingrestenosis, comprising inserting a stent into an obstructed bloodvessel, the stent having a generally tubular structure, the surface ofthe structure being coated with (or otherwise adapted to release) aninventive compound or composition, such that the obstruction iseliminated and the inventive compound or composition is delivered inamounts effective to prevent restenosis and/or reduce the rate ofrestenosis. In other embodiments, methods are provided for preventingrestenosis, comprising inserting a stent into an obstructed bloodvessel, the stent having a generally tubular structure, the surface ofthe structure being coated with (or otherwise adapted to release) aninventive compound or composition, such that the obstruction iseliminated and the inventive compound or composition is delivered inamounts effective to inhibit smooth muscle cell proliferation.

Within other aspects of the present invention, methods are provided forexpanding the lumen of a body passageway, comprising inserting a stentinto the passageway, the stent having a generally tubular structure, thesurface of the structure being coated with (or otherwise adapted torelease) an inventive compound or composition, such that the passagewayis expanded. In certain embodiments, the lumen of a body passageway isexpanded in order to eliminate a biliary, gastrointestinal, esophageal,tracheal/bronchial, urethral and/or vascular obstruction.

In certain embodiments, methods are provided for eliminating biliaryobstructions, comprising inserting a biliary stent into a biliarypassageway, the stent having a generally tubular structure, the surfaceof the structure being coated with (or otherwise adapted to release) aninventive compound or composition, such that the biliary obstruction iseliminated. Briefly, tumor overgrowth of the common bile duct results inprogressive cholestatic jaundice which is incompatible with life.Generally, the biliary system which drains bile from the liver into theduodenum is most often obstructed by (1) a tumor composed of bile ductcells (cholangiocarcinoma), (2) a tumor which invades the bile duct(e.g., pancreatic carcinoma), or (3) a tumor which exerts extrinsicpressure and compresses the bile duct (e.g., enlarged lymph nodes). Bothprimary biliary tumors, as well as other tumors which cause compressionof the biliary tree may be treated utilizing stents Implants and othersurgical or medical devices may be coated with (or otherwise adapted torelease) compositions of the present invention. One example of primarybiliary tumors are adenocarcinomas (which are also called Klatskintumors when found at the bifurcation of the common hepatic duct). Thesetumors are also referred to as biliary carcinomas,choledocholangiocarcinomas, or adenocarcinomas of the biliary system.Benign tumors which affect the bile duct (e.g., adenoma of the biliarysystem), and, in rare cases, squamous cell carcinomas of the bile ductand adenocarcinomas of the gallbladder, may also cause compression ofthe biliary tree and therefore, result in biliary obstruction.Compression of the biliary tree is most commonly due to tumors of theliver and pancreas which compress and therefore obstruct the ducts. Mostof the tumors from the pancreas arise from cells of the pancreaticducts. This is a highly fatal form of cancer (5% of all cancer deaths;26,000 new cases per year in the U.S.) with an average of 6 monthssurvival and a 1 year survival rate of only 10%. When these tumors arelocated in the head of the pancreas they frequently cause biliaryobstruction, and this detracts significantly from the quality of life ofthe patient. While all types of pancreatic tumors are generally referredto as “carcinoma of the pancreas” there are histologic subtypesincluding: adenocarcinoma, adenosquamous carcinoma, cystadenocarcinoma,and acinar cell carcinoma. Hepatic tumors, as discussed above, may alsocause compression of the biliary tree, and therefore cause obstructionof the biliary ducts.

In certain embodiments, a biliary stent is first inserted into a biliarypassageway in one of several ways: from the top end by inserting aneedle through the abdominal wall and through the liver (a percutaneoustranshepatic cholangiogram or “PTC”); from the bottom end by cannulatingthe bile duct through an endoscope inserted through the mouth, stomach,and duodenum (an endoscopic retrograde cholangiogram or “ERCP”); or bydirect incision during a surgical procedure. In certain embodiments, apreinsertion examination, PTC, ERCP, or direct visualization at the timeof surgery is performed to determine the appropriate position for stentinsertion. A guidewire is then advanced through the lesion, and overthis a delivery catheter is passed to allow the stent to be inserted inits collapsed form. If the diagnostic exam was a PTC, the guidewire anddelivery catheter is inserted via the abdominal wall, while if theoriginal exam was an ERCP the stent may be placed via the mouth. Thestent is then positioned under radiologic, endoscopic, or direct visualcontrol taking particular care to place it precisely across thenarrowing in the bile duct. The delivery catheter is then removedleaving the stent standing as a scaffolding which holds the bile ductopen. A further cholangiogram may be performed to document that thestent is appropriately positioned.

In certain embodiments, methods are provided for eliminating esophagealobstructions, comprising inserting an esophageal stent into anesophagus, the stent having a generally tubular structure, the surfaceof the structure being coated with (or otherwise adapted to release) aninventive compound or composition, such that the esophageal obstructionis eliminated. Briefly, the esophagus is the hollow tube whichtransports food and liquids from the mouth to the stomach. Cancer of theesophagus or invasion by cancer arising in adjacent organs (e.g., cancerof the stomach or lung) results in the inability to swallow food orsaliva. In certain embodiments, a preinsertion examination, usually abarium swallow or endoscopy is performed in order to determine theappropriate position for stent insertion. A catheter or endoscope maythen be positioned through the mouth, and a guidewire is advancedthrough the blockage. A stent delivery catheter is passed over theguidewire under radiologic or endoscopic control, and a stent is placedprecisely across the narrowing in the esophagus. A post-insertionexamination, usually a barium swallow x-ray, may be utilized to confirmappropriate positioning.

In certain embodiments, methods are provided for eliminating colonicobstructions, comprising inserting a colonic stent into a colon, thestent having a generally tubular structure, the surface of the structurebeing coated with (or otherwise adapted to release) an inventivecompound or composition, such that the colonic obstruction iseliminated. Briefly, the colon is the hollow tube which transportsdigested food and waste materials from the small intestines to the anus.Cancer of the rectum and/or colon or invasion by cancer arising inadjacent organs (e.g., cancer of the uterus, ovary, bladder) results inthe inability to eliminate feces from the bowel. In certain embodiments,a preinsertion examination, usually a barium enema or colonoscopy isperformed in order to determine the appropriate position for stentinsertion. A catheter or endoscope may then be positioned through theanus, and a guidewire is advanced through the blockage. A stent deliverycatheter is passed over the guidewire under radiologic or endoscopiccontrol, and a stent is placed precisely across the narrowing in thecolon or rectum. A post-insertion examination, usually a barium enemax-ray, may be utilized to confirm appropriate positioning.

In certain embodiments, methods are provided for eliminatingtracheal/bronchial obstructions, comprising inserting atracheal/bronchial stent into a trachea or bronchi, the stent having agenerally tubular structure, the surface of the structure being coatedwith (or otherwise adapted to release) an inventive compound orcomposition, such that the tracheal/bronchial obstruction is eliminated.Briefly, the trachea and bronchi are tubes which carry air from themouth and nose to the lungs. Blockage of the trachea by cancer, invasionby cancer arising in adjacent organs (e.g. cancer of the lung), orcollapse of the trachea or bronchi due to chondromalacia (weakening ofthe cartilage rings) results in inability to breathe. In certainembodiments, preinsertion examination, usually an endoscopy, isperformed in order to determine the appropriate position for stentinsertion. A catheter or endoscope is then positioned through the mouth,and a guidewire advanced through the blockage. A delivery catheter isthen passed over the guidewire in order to allow a collapsed stent to beinserted. The stent is placed under radiologic or endoscopic control inorder to place it precisely across the narrowing. The delivery cathetermay then be removed leaving the stent standing as a scaffold on its own.A post-insertion examination, usually a bronchoscopy may be utilized toconfirm appropriate positioning.

In certain embodiments, methods are provided for eliminating urethralobstructions, comprising inserting a urethral stent into a urethra, thestent having a generally tubular structure, the surface of the structurebeing coated with (or otherwise adapted to release) an inventivecompound or composition, such that the urethral obstruction iseliminated. Briefly, the urethra is the tube which drains the bladderthrough the penis. Extrinsic narrowing of the urethra as it passesthrough the prostate, due to hypertrophy of the prostate, occurs invirtually every man over the age of 60 and causes progressive difficultywith urination. In certain embodiments, a preinsertion examination,usually an endoscopy or urethrogram is first performed in order todetermine the appropriate position for stent insertion, which is abovethe external urinary sphincter at the lower end, and close to flush withthe bladder neck at the upper end. An endoscope or catheter is thenpositioned through the penile opening and a guidewire advanced into thebladder. A delivery catheter is then passed over the guidewire in orderto allow stent insertion. The delivery catheter is then removed, and thestent expanded into place. A post-insertion examination, usuallyendoscopy or retrograde urethrogram, may be utilized to confirmappropriate position.

In certain embodiments, methods are provided for eliminating vascularobstructions, comprising inserting a vascular stent into a blood vessel,the stent having a generally tubular structure, the surface of thestructure being coated with (or otherwise adapted to release) aninventive compound or composition, such that the vascular obstruction iseliminated. Briefly, stents may be placed in a wide array of bloodvessels, both arteries and veins, to prevent recurrent stenosis at thesite of failed angioplasties, to treat narrowings that would likely failif treated with angioplasty, and to treat post-surgical narrowings(e.g., dialysis graft stenosis). Suitable sites include, but ar enotlimited to, the iliac, renal, and coronary arteries, the superior venacava, and in dialysis grafts. In certain embodiments, angiography isfirst performed in order to localize the site for placement of thestent. This is typically accomplished by injecting radiopaque contrastthrough a catheter inserted into an artery or vein as an x-ray is taken.A catheter may then be inserted either percutaneously or by surgery intothe femoral artery, brachial artery, femoral vein, or brachial vein, andadvanced into the appropriate blood vessel by steering it through thevascular system under fluoroscopic guidance. A stent may then bepositioned across the vascular stenosis. A post-insertion angiogram mayalso be utilized in order to confirm appropriate positioning.

Furthermore, after formulation with an appropriate pharmaceuticallyacceptable carrier in a desired dosage, the pharmaceutical compositionsof this invention can be administered to humans and other animalsorally, rectally, parenterally, intracisternally, intravaginally,intraperitoneally, topically (as by powders, ointments, or drops),bucally, as an oral or nasal spray, or the like, depending on theseverity of the infection being treated. In certain embodiments, thecompounds of the invention may be administered at dosage levels of about0.001 mg/kg to about 50 mg/kg, from about 0.01 mg/kg to about 25 mg/kg,or from about 0.1 mg/kg to about 10 mg/kg of subject body weight perday, one or more times a day, to obtain the desired therapeutic effect.It will also be appreciated that dosages smaller than 0.001 mg/kg orgreater than 50 mg/kg (for example 50–100 mg/kg) can be administered toa subject. In certain embodiments, compounds are administered orally orparenterally.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a drug, it is often desirable to slowthe absorption of the drug from subcutaneous or intramuscular injection.This may be accomplished by the use of a liquid suspension orcrystalline or amorphous material with poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolutionthat, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle. Injectable depot forms are made by forming microencapsulematrices of the drug in biodegradable polymers such aspolylactide-polyglycolide. Depending upon the ratio of drug to polymerand the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude (poly(orthoesters) and poly(anhydrides). Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions which are compatible with body tissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar—agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polyethylene glycols and the like.

The active compounds can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose and starch. Such dosage forms may alsocomprise, as in normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such asmagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositionswhich can be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, and eye drops are also contemplatedas being within the scope of this invention. Additionally, the presentinvention contemplates the use of transdermal patches, which have theadded advantage of providing controlled delivery of a compound to thebody. Such dosage forms are made by dissolving or dispensing thecompound in the proper medium. Absorption enhancers can also be used toincrease the flux of the compound across the skin. The rate can becontrolled by either providing a rate controlling membrane or bydispersing the compound in a polymer matrix or gel.

It will also be appreciated that the compounds and pharmaceuticalcompositions of the present invention can be formulated and employed incombination therapies, that is, the compounds and pharmaceuticalcompositions can be formulated with or administered concurrently with,prior to, or subsequent to, one or more other desired therapeutics ormedical procedures. The particular combination of therapies(therapeutics or procedures) to employ in a combination regimen willtake into account compatibility of the desired therapeutics and/orprocedures and the desired therapeutic effect to be achieved. It willalso be appreciated that the therapies employed may achieve a desiredeffect for the same disorder (for example, an inventive compound may beadministered concurrently with another anticancer agent), or they mayachieve different effects (e.g., control of any adverse effects). Forexample, other therapies or anticancer agents that may be used incombination with the inventive anticancer agents of the presentinvention include surgery, radiotherapy (in but a few examples,γ-radiation, neutron beam radiotherapy, electron beam radiotherapy,proton therapy, brachytherapy, and systemic radioactive isotopes, toname a few), endocrine therapy, biologic response modifiers(interferons, interleukins, and tumor necrosis factor (TNF) to name afew), hyperthermia and cryotherapy, agents to attenuate any adverseeffects (e.g., antiemetics), and other approved chemotherapeutic drugs,including, but not limited to, alkylating drugs (mechlorethamine,chlorambucil, Cyclophosphamide, Melphalan, Ifosfamide), antimetabolites(Methotrexate), purine antagonists and pyrimidine antagonists(6-Mercaptopurine, 5-Fluorouracil, Cytarabile, Gemcitabine), spindlepoisons (Vinblastine, Vincristine, Vinorelbine, Paclitaxel),podophyllotoxins (Etoposide, Irinotecan, Topotecan), antibiotics(Doxorubicin, Bleomycin, Mitomycin), nitrosoureas (Carmustine,Lomustine), inorganic ions (Cisplatin, Carboplatin), enzymes(Asparaginase), and hormones (Tamoxifen, Leuprolide, Flutamide, andMegestrol), to name a few. For a more comprehensive discussion ofupdated cancer therapies see, The Merck Manual, Seventeenth Ed. 1999,the entire contents of which are hereby incorporated by reference. Seealso the National Cancer Institute (NCI) website (www.nci.nih.gov) andthe Food and Drug Administration (FDA) website for a list of the FDAapproved oncology drugs (www.fda.gov/cder/cancer/druglistframe—SeeAppendix A).

In certain embodiments, the pharmaceutical compositions of the presentinvention further comprise one or more additional therapeutically activeingredients (e.g., chemotherapeutic and/or palliative). For purposes ofthe invention, the term “Palliative” refers to treatment that is focusedon the relief of symptoms of a disease and/or side effects of atherapeutic regimen, but is not curative. For example, palliativetreatment encompasses painkillers, antinausea medications andanti-sickness drugs. In addition, chemotherapy, radiotherapy and surgerycan all be used palliatively (that is, to reduce symptoms without goingfor cure; e.g., for shrinking tumors and reducing pressure, bleeding,pain and other symptoms of cancer).

Treatment Kits

In other embodiments, the present invention relates to a kit forconveniently and effectively carrying out the methods in accordance withthe present invention. In general, the pharmaceutical pack or kitcomprises one or more containers filled with one or more of theingredients of the pharmaceutical compositions of the invention. Suchkits are especially suited for the delivery of solid oral forms such astablets or capsules. Such a kit preferably includes a number of unitdosages, and may also include a card having the dosages oriented in theorder of their intended use. If desired, a memory aid can be provided,for example in the form of numbers, letters, or other markings or with acalendar insert, designating the days in the treatment schedule in whichthe dosages can be administered. Alternatively, placebo dosages, orcalcium dietary supplements, either in a form similar to or distinctfrom the dosages of the pharmaceutical compositions, can be included toprovide a kit in which a dosage is taken every day. Optionallyassociated with such container(s) can be a notice in the form prescribedby a governmental agency regulating the manufacture, use or sale ofpharmaceutical products, which notice reflects approval by the agency ofmanufacture, use or sale for human administration.

Equivalents

The representative examples that follow are intended to help illustratethe invention, and are not intended to, nor should they be construed to,limit the scope of the invention. Indeed, various modifications of theinvention and many further embodiments thereof, in addition to thoseshown and described herein, will become apparent to those skilled in theart from the full contents of this document, including the exampleswhich follow and the references to the scientific and patent literaturecited herein. It should further be appreciated that the contents ofthose cited references are incorporated herein by reference to helpillustrate the state of the art.

The following examples contain important additional information,exemplification and guidance that can be adapted to the practice of thisinvention in its various embodiments and the equivalents thereof.

Exemplification

The practitioner has a well-established literature of peptide chemistryto draw upon, in combination with the information contained herein, forguidance on synthetic strategies, protecting groups, and other materialsand methods useful for the synthesis of the compounds of this invention.

The various references cited herein provide helpful backgroundinformation on preparing compounds similar to the inventive compoundsdescribed herein or relevant intermediates, as well as information onformulation, uses, and administration of such compounds which may be ofinterest.

Moreover, the practitioner is directed to the specific guidance andexamples provided in this document relating to various exemplarycompounds and intermediates thereof.

The compounds of this invention and their preparation can be understoodfurther by the examples that illustrate some of the processes by whichthese compounds are prepared or used. It will be appreciated, however,that these examples do not limit the invention. Variations of theinvention, now known or further developed, are considered to fall withinthe scope of the present invention as described herein and ashereinafter claimed.

According to the present invention, any available techniques can be usedto make or prepare the inventive compounds or compositions includingthem. For example, a variety of solution phase synthetic methods such asthose discussed in detail below may be used. Alternatively oradditionally, the inventive compounds may be prepared using any of avariety combinatorial techniques, parallel synthesis and/or solid phasesynthetic methods known in the art.

It will be appreciated as described below, that a variety of inventivecompounds can be synthesized according to the methods described herein.The starting materials and reagents used in preparing these compoundsare either available from commercial suppliers such as Aldrich ChemicalCompany (Milwaukee, Wis.), Bachem (Torrance, Calif.), Sigma (St. Louis,Mo.), or are prepared by methods well known to a person of ordinaryskill in the art following procedures described in such references asFieser and Fieser 1991, “Reagents for Organic Synthesis”, vols 1–17,John Wiley and Sons, New York, N.Y., 1991; Rodd 1989 “Chemistry ofCarbon Compounds”, vols. 1–5 and supps, Elsevier Science Publishers,1989; “Organic Reactions”, vols 1–40, John Wiley and Sons, New York,N.Y., 1991; March 2001, “Advanced Organic Chemistry”, 5th ed. John Wileyand Sons, New York, N.Y.; and Larock 1990, “Comprehensive OrganicTransformations: A Guide to Functional Group Preparations”, 2^(nd) ed.VCH Publishers. These schemes are merely illustrative of some methods bywhich the compounds of this invention can be synthesized, and variousmodifications to these schemes can be made and will be suggested to aperson of ordinary skill in the art having regard to this disclosure.

The starting materials, intermediates, and compounds of this inventionmay be isolated and purified using conventional techniques, includingfiltration, distillation, crystallization, chromatography, and the like.They may be characterized using conventional methods, including physicalconstants and spectral data.

Certain exemplary compounds of the invention are listed below and arereferred to by compound number as indicated.

Compound Structure ER-803840(HEMIASTERLIN)

ER-803887

ER-803888

ER-803889

ER-803890

ER-803921

ER-803995

ER-803996

ER-803997Higher Rf diastereomer

ER-803998Lower Rf diastereomer

ER-803999

ER-804000

ER-804001

ER-804002

ER-804332

ER-804333

ER-804334

ER-804635

ER-804636

ER-804762

ER-805206

ER-805230

ER-805231

ER-805257

ER-805258

ER-805268

ER-805316

ER-805324

ER-805532

ER-805590

ER-805594

ER-805599

ER-805697

ER-805701

ER-805711

ER-805713

ER-805734

ER-805735

ER-805736

ER-805738

ER-805847

ER-805865

ER-805876

ER-805913

ER-805914

ER-805925

ER-805938

ER-805968

ER-805974

ER-806004

ER-806005

ER-806021

ER-806022

ER-806023

ER-806031

ER-806032

ER-806073

ER-806085

ER-806086

ER-806105

ER-806110

ER-806119

ER-806135

ER-806147

ER-806180

ER-806223

ER-806318

ER-806356

ER-806371

ER-806395

ER-806396

ER-806397

ER-806398

ER-806399

ER-806400

ER-806409

ER-806418

ER-806713

ER-806717

ER-806718

ER-806735

ER-806748

ER-806749

ER-806791

ER-806792

ER-806793

ER-806794

ER-806822

ER-806823

ER-806824

ER-806825

ER-806830

ER-806831

ER-806853

ER-806854

ER-806861

ER-806862

ER-806863

ER-806864

ER-806865

ER-806866

ER-806867

ER-806868

ER-806869

ER-806870

ER-806871

ER-806879

ER-806880

ER-806881

ER-806882

ER-806920

ER-806921

ER-806922

ER-806923

ER-806924

ER-806925

ER-807000

ER-807001

ER-807002

ER-807077single diastereomer

ER-807078single diastereomer

ER-807079

ER-807080

ER-807081single diastereomer

ER-807096

ER-807101

ER-807102

ER-807133

ER-807134

ER-807135

ER-807145

ER-807146

ER-807147

ER-807148

ER-807160

ER-807161

ER-807180

ER-807192

ER-807193

ER-807194

ER-807195

ER-807209

ER-807210

ER-807212

ER-807213

ER-807214

ER-807215

ER-807217

ER-807218

ER-807219

ER-807222

ER-807226

ER-807228

ER-807229

ER-807230

ER-807231

ER-807232

ER-807237

ER-807238

ER-807246

ER-807247

ER-807248

ER-807249

ER-807303

ER-807324

ER-807328

ER-807329

ER-807332

ER-807334

ER-807339

ER-807341

ER-807342

ER-807343

ER-807344

ER-807345

ER-807346

ER-807347

ER-807352

ER-807353

ER-807354

ER-807355

ER-807360

ER-807361

R-807362

ER-807364

ER-807365

ER-807366

ER-807370

ER-807371

ER-807374

ER-807375

ER-807393

ER-807413

ER-807414

ER-807417

ER-807418

ER-807419

ER-807420

ER-807421

ER-807431

ER-807461

ER-807470single diastereomer

ER-807471single diastereomer

ER-807480single diastereomer

ER-807481single diastereomer

ER-807482single diastereomer

ER-807483single diastereomer

ER-807484

ER-807487

ER-807494

ER-807495

ER-807499

ER-807500

ER-807501

ER-807502

ER-807503

ER-807504

ER-807529

ER-807530

ER-807533

ER-807534

ER-807535

ER-807540

ER-807541

ER-807542

ER-807575

ER-807576

ER-807577

ER-807602

ER-807603

ER-807619

ER-807620

ER-807621

ER-807622

ER-807625

ER-807626

ER-807739

ER-807740

ER-807742

ER-807743

ER-807744

ER-807745

ER-807760

ER-807761

ER-807796Trans-substituents on thepiperidine ring, butabsolutestereochemistry is unknown.Single diastereomer.

ER-807797Trans-substituents on thepiperidine ring, butabsolutestereochemistry is unknown.Single diastereomer.

ER-807798

ER-807799Mixture of two diastereomers

ER-807800

ER-807801

ER-807802

ER-807803

ER-807804

ER-807805

ER-807806

ER-807807

ER-807808

ER-807809

ER-807810

ER-807811

ER-807812

ER-807820single diastereomer

ER-807821single diastereomer

ER-807829

ER-807830

ER-807831

ER-807832

ER-807833

ER-807839

ER-807840

ER-807842

ER-807844

ER-807846

ER-807850

ER-807860

ER-807861

ER-807863Cis-substituents on thepiperidine ring, butabsolutestereochemistry is unknown.Single diastereomer.

ER-807864Cis-substituents on thepiperidine ring, butabsolutestereochemistry is unknown.Single diastereomer.

ER-807874

ER-807875

ER-807877Cis-substituents on thepiperidine ring. Twodiastereomers (4:1).

ER-807880

ER-807881

ER-807882

ER-807883

ER-807884

ER-807885

ER-807886

ER-807888

ER-807889

ER-807890

ER-807891

ER-807899

ER-807900

ER-807902

ER-807904

ER-807905

ER-807906

ER-807907

ER-807908

ER-807909

ER-807911

ER-807944

ER-807945

ER-807947

ER-807948

ER-807949

ER-807950

ER-807951

ER-807953

ER-807954

ER-807959Cis-substituents on thepiperidine ring, butabsolutestereochemistry is unknown.Single diastereomer.

ER-807960Cis-substituents on thepiperidine ring, butabsolutestereochemistry is unknown.Single diastereomer.

ER-807961

ER-807963

ER-807973

ER-807974

ER-807975

ER-807981

ER-807982

ER-807983

ER-807986

ER-807987

ER-807988

ER-807989

ER-807990

ER-807991

ER-807992

ER-807994

ER-807995

ER-807996

ER-807997

ER-807998

ER-807999

ER-808000

ER-808001

ER-808002

ER-808007

ER-808008

ER-808010

ER-808011

ER-808012

ER-808013

ER-808029

ER-808030

ER-808031

ER-808032

ER-808033

ER-808034

ER-808035

ER-808037

ER-808038

ER-898057

ER-808058

ER-808059

ER-808060

ER-808061

ER-808062

ER-808063

ER-808065Trans-substituents on thepiperidine ring, butabsolutestereochemistry is unknown.Single diastereorner.

ER-808066Trans-substituents on thepiperidine ring, butabsolutestereochemistry is unknown.Single diastereorner.

ER-808067Trans-substituents on thepiperidine ring, butabsolutestereochemistry is unknown.Single diastereorner.

ER-808068Trans-substituents on thepiperidine ring, butabsolutestereochemistry is unknown.Single diastereorner.

ER-808071Trans-substituents on thepiperidine ring, butabsolutestereochemistry is unknown.Single diastereorner.

ER-808072Trans-substituents on thepiperidine ring, butabsolutestereochemistry is unknown.Single diastereorner.

ER-808073Trans-substituents on thepiperidine ring, butabsolutestereochemistry is unknown.Single diastereorner.

ER-808074Trans-substituents on thepiperidine ring, butabsolutestereochemistry is unknown.Single diastereorner.

ER-808075

ER-808076

ER-808077

ER-808108

ER-808109

ER-808110

ER-808111

ER-808112

ER-808113

ER-808114

ER-808115

ER-808116

ER-808117

ER-808118

ER-808119

ER-808120

ER-808121

ER-808122

ER-808123

ER-808124

ER-808125

ER-808126Absolute stereochemistry isunknown. Single diastereomer

ER-808131

ER-808139

ER-808140

ER-808141

ER-808142

ER-808143

ER-808144

ER-808145

ER-808146

ER-808147

ER-808148

ER-808149

ER-808150

ER-808161

ER-808166

ER-808167

ER-808168

ER-808169

ER-808170

ER-808171

ER-808172

ER-808173

ER-808174

ER-808175

ER-808176

ER-808177

ER-808178

ER-808179

ER-808180

ER-808181

ER-808182

ER-808183

ER-808189

ER-808190

ER-808191

ER-808192

ER-808193

ER-808194

ET-808195

ER-808196

ER-808197

ER-808198

ER-808199

ER-808200

ER-808201

ER-808202

ER-808203

ER-808204Cis-substituents on thepiperidine ring, butabsolutestereochemistry is unknown.Single diastereomer

ER-808205Cis-substituents on thepiperidine ring, butabsolutestereochemistry is unknown.Single diastereomer

ER-808206

ER-808207

ER-808208

ER-808209

ER-808210

ER-808211

ER-808212

ER-808213

ER-808214

ER-808215

ER-808216

ER-808217

ER-808218

ER-808219

ER-808220

ER-808221

ER-808222

ER-808223

ER-808224

ER-808225

ER-808226

ER-808248

ER-808249

ER-808251

ER-808253

ER-808292

ER-808293

ER-808294

ER-808295

ER-808296

ER-808297

ER-808298

ER-808299

ER-808300

ER-808301-

ER-808302

ER-808303

ER-808304

ER-808305

ER-808306

ER-808307

ER-808308

ER-808309

ER-808323

ER-808324

ER-808325

ER-808326

ER-808328

ER-808329

ER-808330

ER-808331

ER-808332

ER-808333

ER-808334

ER-808335

ER-808336

ER-808337

ER-808338

ER-808339

ER-808340

ER-808341

ER-808342

ER-808343

ER-808344

ER-808345

ER-808357single diastereomer

ER-808358single diastereomer

ER-808359single diastereomer

ER-808366single diastereomer

ER-808367

ER-808368

ER-808383

ER-808384

ER-808389

ER-808390

ER-808391

ER-808392

ER-808393

ER-808394

ER-808395

ER-808396

ER-808397

ER-808398

ER-808399

ER-808400

ER-808401

ER-808402

ER-808403

ER-808404

ER-808433

ER-808434

ER-808435

ER-808436

ER-808437

ER-808447Cis-substituents on thepiperidine ring, butabsolutestereochemistry is unknown.Single diastereomer

ER-808448Cis-substituents on thepiperidine ring, butabsolutestereochemistry is unknown.Single diastereomer

ER-808449Cis-substituents on thepiperidine ring, butabsolutestereochemistry is unknown.Single diastereomer

ER-808450Cis-substituents on thepiperidine ring, butabsolutestereochemistry is unknown.Single diastereomer

ER-808451Cis-substituents on thepiperidine ring, butabsolutestereochemistry is unknown.Single diastereomer

ER-808452Cis-substituents on thepiperidine ring, butabsolutestereochemistry is unknown.Single diastereomer

ER-808453Cis-substituents on thepiperidine ring, butabsolutestereochemistry is unknown.Single diastereomer

ER-808454Cis-substituents on thepiperidine ring, butabsolutestereochemistry is unknown.Single diastereomer

ER-808475single diastereomer

ER-808476single diastereomer

ER-808477single diastereomer

ER-808478single diastereomer

ER-808479

ER-808480

ER-808481

ER-808482

ER-808483

ER-808484

ER-808485

ER-808486

ER-808487

ER-808488

ER-808489

ER-808490

ER-808491Single diastereomer

ER-808492Single diastereomer

ER-808493Single diastereomer

ER-808494Single diastereomer

ER-808495

ER-808552

ER-808553

ER-808563

ER-808564

ER-808565

ER-808566

ER-808567

ER-808568

ER-808609

ER-808610

ER-808656Single diastereomer

ER-808662Single diastereomer

ER-808674

ER-808676

ER-808677

ER-808678

ER-808679

ER-808680

ER-808681

ER-808682

ER-808683

ER-808684

ER-808685

ER-808686

ER-808687

ER-808688

ER-808689

ER-808690

ER-808693

ER-808694

ER-808695

ER-808696

ER-808697

ER-808698

ER-808699

ER-808700

ER-808706Single diastereomer

ER-808707Single diastereomer

ER-808708Single diastereomer

ER-80870Single diastereomer

ER-808710Single diastereomer

ER-808731

ER-808732

ER-808774Single diastereomer

ER-808775Single diastereomer

ER-808777Single diastereomer

ER-808779Single diastereomer

ER-808780Single diastereomer

ER-808815Single diastereomer

ER-808816Single diastereomer

ER-808817Single diastereomer

ER-808818Cis-substituents on thepiperidine ring, butabsolutestereochemistry is unknown.Single diastereomer

ER-808819Cis-substituents on thepiperidine ring, butabsolutestereochemistry is unknown.Single diastereomer

ER-808820Cis-substituents on thepiperidine ring, butabsolutestereochemistry is unknown.Single diastereomer

ER-808821Cis-substituents on thepiperidine ring, butabsolutestereochemistry is unknown.Single diastereomer

ER-808822Cis-substituents on thepiperidine ring, butabsolutestereochemistry is unknown.Single diastereomer

ER-808823Cis-substituents on thepiperidine ring, butabsolutestereochemistry is unknown.Single diastereomer

ER-808824

ER-808825

ER-808826Single diastereomer

ER-808827Cis-substituents on thepiperidine ring, butabsolutestereochemistry is unknown.Single diastereomer

ER-808828Cis-substituents on thepiperidine ring, butabsolutestereochemistry is unknown.Single diastereomer

ER-808829Cis-substituents on thepiperidine ring, butabsolutestereochemistry is unknown.Single diastereomer

ER-808830Cis-substituents on thepiperidine ring, butabsolutestereochemistry is unknown.Single diastereomer

ER-808831Cis-substituents on thepiperidine ring, butabsolutestereochemistry is unknown.Single diastereomer

ER-808832Cis-substituents on thepiperidine ring, butabsolutestereochemistry is unknown.Single diastereomer

ER-808861

ER-808862

ER-808863

ER-808864

ER-808865

ER-808866

ER-808867

ER-808868

ER-808869

ER-808870

ER-808871

ER-808872

ER-808873

ER-808874

ER-808875

ER-808876

ER-808877

ER-808878

ER-808879

ER-808880

ER-808881

ER-808882

ER-808883

ER-808884

ER-808885

ER-808886

ER-808887

ER-808888

ER-808889

ER-808890

ER-808891

ER-808892

ER-808893

ER-808894

ER-808895

ER-808896

ER-808897

ER-808898

ER-808899

ER-808900

ER-808901

ER-808902

ER-808903

ER-808904

ER-808905

ER-808906

ER-808907

ER-808908

ER-808909

ER-808910

ER-808911

ER-808912

ER-808913

ER-808914

ER-808915

ER-808916

ER-808917

ER-808918

ER-808919

ER-808920

ER-808921

ER-808922

ER-808923

ER-808987

ER-808988

ER-808990

ER-809040Single diastereomer

ER-809041

ER-809043

ER-809044

ER-809045Single diastereomer

ER-809046

ER-809054

ER-809055

ER-809056

ER-809057

ER-809058

ER-809059

ER-809060

ER-809061

ER-809062

ER-809063

ER-809064

ER-809065

ER-809066

ER-809067

ER-809068

ER-809069

ER-809070

ER-809071

ER-809072

ER-809073

ER-809074

ER-809075

ER-809076

ER-809077

ER-809078

ER-809079

ER-809080

ER-809081

ER-809082

ER-809083

ER-809084

ER-809085

ER-809086

ER-809087

ER-809088

ER-809089

ER-809090

ER-809091

ER-809092

ER-809093

ER-809094

ER-809095

ER-809096

ER-809097

ER-809098

ER-809099

ER-809100

ER-809101

ER-809102

ER-809103

ER-809104

ER-809105

ER-809106

ER-809107

ER-809108

ER-809109

ER-809110

ER-809111

ER-809112

ER-809113

ER-809114

ER-809115

ER-809116

ER-809117

ER-809118

ER-809119

ER-809120

ER-809121

ER-809122

ER-809123

ER-809124

ER-809125

ER-809126

ER-809127

ER-809128

ER-809129

ER-809130

ER-809131

ER-809132

ER-809133

ER-809134

ER-809135

ER-809136

ER-809137

ER-809138

ER-809139

ER-809140

ER-809141

ER-809142

ER-809143

ER-809144

ER-809145

ER-809146

ER-809147

ER-809148

ER-809149

ER-809150

ER-809151

ER-809152

ER-809153

ER-809154

ER-809155

ER-809156

ER-809157

ER-809158

ER-809159

ER-809160

ER-809161

ER-809162

ER-809163

ER-809164

ER-809165

ER-809166

ER-809167

ER-809240

ER-809241

ER-809242

ER-809243

ER-809244

ER-809245

ER-809246

ER-809247

ER-809268

ER-809269

ER-809282

ER-809283

ER-809284

ER-809285

ER-809300

ER-809301

ER-809302

ER-809303

ER-809304

ER-809305

ER-809306

ER-809308

ER-809309

ER-809310

ER-809311

ER-809312

ER-809313

ER-809314

ER-809315

ER-809316

ER-809317

ER-809318

ER-809319

ER-809320

ER-809321

ER-809322

ER-809323

ER-809324

ER-809325

ER-809326

ER-809638

ER-809640

ER-809641Single diastereomer

ER-809642Single diastereomer

ER-809643Single diastereomer

ER-809644Single diastereomer

ER-809645

ER-809646

ER-809647Single diastereomer

ER-809648Single diastereomer

ER-809649Single diastereomer

ER-809650Single diastereomer

General Reaction Procedures:

Unless mentioned specifically, reaction mixtures were stirred using amagnetically driven stirrer bar. An inert atmosphere refers to eitherdry argon or dry nitrogen. Reactions were monitored either by thin layerchromatography (TLC), by proton nuclear magnetic resonance or byhigh-pressure liquid chromatography (HPLC), of a suitably worked upsample of the reaction mixture.

Listed below are abbreviations used for some common organic reagentsreferred to herein:

BOC or Di-tert-Butyl dicarbonate BOC₂O: CMC:1-Cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p- toluenesulfonateDCM: Dichloromethane DEPC: Diethylphosphoryl cyanide (Diethylcyanophosphonate) DIBAL: Diisobutylaluminum hydride DIEA:Diisopropylethylamine DMF: N,N-Dimethylformamide DMSO: DimethylsulfoxideEther: Diethyl ether HBTU:O-(1-H-benzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphateHOAt: 1-Hydroxy-7-azabenzotriazole LAH: Lithium aluminum hydride MSA:Methane sulfonic acid NMM: N-Methyl Morpholine TBME: Tert-butyl methylether TFA: Trifluoroacetic acid THF: Tetrahydrofuran TMEDA:Tetramethylethylenediamine

General Work Up Procedures:

Unless mentioned specifically, reaction mixtures were cooled to roomtemperature or below then quenched, when necessary, with either water ora saturated aqueous solution of ammonium chloride. Desired products wereextracted by partitioning between water and a suitable water-immisciblesolvent (eg. ethyl acetate, dichloromethane, diethyl ether). The desiredproduct containing extracts were washed appropriately with waterfollowed by a saturated solution of brine. On occasions where theproduct containing extract was deemed to contain residual oxidants, theextract was washed with a 10% solution of sodium thiosulphate insaturated aqueous sodium bicarbonate solution, prior to theaforementioned washing procedure. On occasions where the productcontaining extract was deemed to contain residual acids, the extract waswashed with saturated aqueous sodium bicarbonate solution, prior to theaforementioned washing procedure (except in those cases where thedesired product itself had acidic character). On occasions where theproduct containing extract was deemed to contain residual bases, theextract was washed with 10% aqueous citric acid solution, prior to theaforementioned washing procedure (except in those cases where thedesired product itself had basic character). Post washing, the desiredproduct containing extracts were dried over anhydrous magnesiumsulphate, then filtered. The crude products were then isolated byremoval of solvent(s) by rotary evaporation under reduced pressure, atan appropriate temperature (generally less than 45° C.).

On occasions where triphenylphosphine oxide was a major byproduct of thereaction, the reaction mixture was added directly to a large volume ofwell-stirred hexane. The resultant precipitate of triphenylphosphineoxide was removed by filtration and the filtrate processed in the usualmanner.

General Purification Procedures:

Chromatographic purification refers either to flash columnchromatography on silica, using a single solvent or mixed solvent aseluent, or HPLC on a C18 column. Suitably purified desired productcontaining elutes were combined and concentrated under reduced pressureat an appropriate temperature (generally less than 45° C.) to constantmass. Final compounds were prepared for biological testing by either a)dissolved in 50% aqueous acetonitrile, filtered and transferred tovials, then freeze-dried under high vacuum; or b) dissolved in methanol,filtered and transferred to vials, then concentrated to dryness using aCentrifugal vacuum evaporator.

EXAMPLE 1

Preparation of Amine Esters 18, Amine Acids 20 and Amine Amides 23

Preparation of Compound 13

To a solution of Compound 12 (205 mg) in DMF (3.8 ml), at roomtemperature, was added (S)-N-Boc-neo-phenylalanine (6) (140 mg), NMM(0.30 ml), HOAt (0.124 g), and CMC (1.166 g). The reaction mixture wasshaken at room temperature for 24 hr. Aqueous workup followed bychromatographic purification gave Compound 13 (153 mg, 61%).

Preparation of Compound 14

To a solution of compound 13 (153 mg) in methanol (20 ml), at 0° C., wasadded sodium borohydride (3.18 g) portionwise with shaking over a 3 dayperiod. The reaction mixture temperature was maintained between 0°–5° C.On occasion where the reaction mixture turned into a solidified mass,THF was added to aid agitation. The reaction mixture was allowed to warmto room temperature then re-cooled to 0° C. and worked up in the usualmanner to give compound 14 (140 mg, 96%).

Preparation of Compound 15

To a solution of compound 14 (50 mg) in THF (3 ml), at room temperature,was added Dess Martin periodinane (204 mg) in one portion. The resultantsuspension was stirred vigorously for 4.5 hr. An aqueous work up gavecrude compound 15 (50 mg) which was used immediately in the next stagewithout purification.

General Procedure for the Preparation of Amine Esters 18

To a solution of compound 15 (1 equivalent) in a suitable volume of1,2-dichloroethane, at room temperature, was added 4A molecular sieves(crushed and dried) (equal mass to that of the amine hydrochloride). Asuitably chosen amine hydrochloride (16) (10 equivalents) was added withvigorous stirring followed by sodium triacetoxyborohydride (1.5equivalents). The reaction mixture was stirred at an appropriatetemperature (20°–50° C.) until compound 15 was consumed to asatisfactory degree. Aqueous work up followed by chromatographicpurification gave the corresponding N-Boc Amine Ester 17. Deprotectionof the N-Boc moiety under suitable conditions would give thecorresponding N-terminal free amine 18.

General Procedure for the Preparation of Amine Acids 20

To a solution of the N-Boc Amine Ester 17 in a suitable mixture of THFand methanol, was added 1M lithium hydroxide solution (10–50equivalents). When the N-Boc Amine Ester 17 was hydrolyzed to asatisfactory degree, the reaction mixture was given an aqueous work up.The N-Boc Amine Acid 19 was purified chromatographically. Deprotectionof the N-Boc moiety under suitable conditions would give thecorresponding N-terminal free amine 20.

General Procedure for the Preparation of Amine Amides 23

To a solution of the N-Boc Anine Acid 19 in DMF, at room temperature,was added NMM (20 equivalents). A suitably chosen anine hydrochloride(21) (20 equivalents) was added followed by DEPC (20 equivalents). Whenthe N-Boc Canine Acid 19 was consumed to a satisfactory degree the N-BocAmine Amide 22 was isolated either by direct chromatographicpurification of the reaction mixture, or by an aqueous work up followedby chromatographic purification. Deprotection of the N-Boc moiety undersuitable conditions would give the corresponding N-terminal free amine23.

EXAMPLE 2

Preparation of N-Acetyl Amine Amides 27

Preparation of Compound 24

To a solution of aldehyde 13 (50 mg) in 1,2-dichloroethane (2 ml), atroom temperature, was added 4A molecular sieves (crushed and dried) (50mg). Glycine methyl ester hydrochloride (120 mg) was added with vigorousstirring followed by sodium triacetoxyborohydride (205 mg). The reactionmixture was stirred at 40° C.) for two hours. Aqueous work up followedby chromatographic purification gave compound 24 (31 mg, 46%).

Preparation of Compound 25

To a solution of compound 24 (5.5 mg) in DMF (0.4 ml), at roomtemperature, was added pyridine (0.006 ml) followed by acetic anhydride(0.004 ml). The reaction mixture was shaken for three hours at roomtemperature then concentrated in vacuo to dryness. The residue wasdissolved in saturated HCl in methanol (1 ml) and stood at roomtemperature for 15 minutes. The reaction mixture was concentrated invacuo to give compound 25 (4 mg, 90%).

Preparation of Compound 26

To a solution of compound 25 (3.35 mg) in methanol (0.2 mL), was added 1M lithium hydroxide solution (0.118 mL). The reaction mixture wasstirred at room temperature for 5 hr. Chromatographic purificationfollowed by treatment with methanolic HCl gave the hydrochloride salt ofcompound 26 (1.95 mg, 61%).

General Procedure for the Preparation of N-Acetyl Amine Amides 27

To a solution of compound 26 (1 equivalent) in DMF, at room temperature,was added NMM (20 equivalents). A suitably chosen amine hydrochloride(21) (20 equivalents) was added followed by DEPC (20 equivalents). Whencompound 26 was consumed to a satisfactory degree the N-Acetyl AmineAmide (27) was isolated by direct chromatographic purification of thereaction mixture.

EXAMPLE 3

Preparation of Compound 33

Preparation of Compound 28

To a solution of compound 3b (1.94 g) in dry DCM (20 mL), at 0° C. underan inert atmosphere, was added a 1 M solution of DIBAL (32 mL) dropwise.The reaction mixture was stirred at 0° C. for 2.5 hr then methanol (4.4mL) was added dropwise followed by a saturated solution of ammoniumchloride (8.8 mL). DCM (200 mL) was added and the reaction mixturestirred vigorously at room temperature for 30 min. Filtration followedby concentrated in vacuo gave crude compound 28 (1.08 g, 65%).

Preparation of Compound 29

To a solution of compound 28 (207 mg) in THF (5 mL), at 0° C. under aninert atmosphere, was added sodium hydride (60% dispersion in mineraloil; 160 mg) portionwise. The reaction mixture was stirred at 0° C. for45 min then treated with ethyl bromoacetate (0.47 mL). The reactionmixture was allowed to warm to room temperature. An aqueous work upfollowed by chromatographic purification gave an intermediate Boccompound (185 mg, 67%). The intermediate Boc compound (139 mg) wasdissolved in ethanol (2 mL) and treated with saturated HCl in ethanol (2mL). The reaction mixture was stood at room temperature for 10 min thenconcentrated in vacuo to dryness to give compound 29 (114 mg).

Preparation of Compound 30

To a solution of compound 29 (114 mg) in DMF (1.8 mL), at roomtemperature, was added (S)-N-Boc-tert-leucine (4) (283 mg), NMM (0.135mL), HOAt (56 mg), and CMC (518 mg). The reaction mixture was shaken atroom temperature for 16 hr. Aqueous workup followed by chromatographicpurification gave an intermediate Boc compound (42 mg, 22%). Theintermediate Boc compound (42 mg) was dissolved in saturated HCl inethanol (5 mL) and stood at room temperature for 1 min. Concentration invacuo gave compound 30 (37 mg).

Preparation of Compound 31

To a solution of compound 30 (24 mg) in DMF (0.26 mL), at roomtemperature, was added (S)-N-Boc-neo-phenylalanine (6) (38 mg), NMM(0.014 mL), HOAt (8.3 mg), and CMC (52 mg). The reaction mixture wasshaken at room temperature for 16 hr. Aqueous workup followed bychromatographic purification gave an intermediate Boc compound (38 mg,64%). The intermediate Boc compound (38 mg) was dissolved in saturatedHCl in ethanol (5 mL) and stood at room temperature for 10 min.Concentration in vacuo gave compound 31 as its HCl salt.

Preparation of Compound 32

A solution of compound 31 (4 mg) in ethanol (2 mL) was treated with 1 Mlithium hydroxide (0.5 ml). The reaction mixture was stirred at roomtemperature for 1.5 hr. Aqueous work up followed by chromatographicpurification gave compound 32 (2.9 mg, 76%).

Preparation of Compound 33

To a solution of compound 32 (1.9 mg) in DMF (70 μl), at roomtemperature, was added NMM (3.8 μl), pyrrolidine (2.8 μl), and DEPC (5.2μl). The reaction mixture was stirred at room temperature for 16 hr. Thereaction mixture was purified chromatographically to give compound 33(1.2 mg, 58%).

EXAMPLE 4

Preparation of Amine Esters 42, Amine Acids 43 and Amine Amides 45

Preparation of Compound 39

To a solution of compound 12 (1.25 g) in DMF (21 mL), at roomtemperature, was added (R)-N-methylpipecoline hydrochloride (38) (0.38g), NMM (1.4 mL), HOAt (0.575 g), and CMC (5.37 g). The reaction mixturewas shaken at room temperature for 24 hr. Aqueous workup gave compound39 (0.511 g, 63%).

Preparation of Compound 40

To a solution of compound 0.39 (0.8 g) in methanol (8 mL), at 0° C., wasadded sodium borohydride (7.9 g) portionwise over a 3 day period. Thereaction mixture temperature was maintained between 0°–5° C. On occasionwhere the reaction mixture turned into a solidified mass, THF was addedto aid stirring. The reaction mixture was allowed to warm to roomtemperature then re-cooled to 0° C. and quenched with saturated sodiumbicarbonate solution. Aqueous workup gave compound 40.

Preparation of Compound 41

To a solution of compound 40 (50 mg) in THF (3 mL), at room temperature,was added Dess Martin periodinane (225 mg) in one portion. The resultantsuspension was stirred vigorously for 4 hr. An aqueous work up gavecrude compound 41 (55 mg) which was used immediately in the next stagewithout purification.

General Procedure for the Preparation of N-terminal N-heterocyclic AmineEsters 42

To a solution of compound 41 (300 mg) in 1,2-dichloroethane (10 mL), atroom temperature, was added 4 A molecular sieves (crushed and dried)(1.5 g). The amino acid ester hydrochloride (16) (10 equivalents) wasadded and the reaction mixture stirred vigorously for ˜10 min. Sodiumtriacetoxyborohydride (290 mg) was added in one portion and the reactionmixture stirred vigorously at room temperature. When compound 41 wasconsumed to a satisfactory degree, the reaction mixture was given anaqueous work up. The N-terminal N-heterocyclic Amine Esters 42 waspurified chromatographically, except in cases where it was deemedunnecessary.

General Procedure for the Preparation of N-terminal N-heterocyclic AmineAcids 43

To a solution of the N-terminal N-heterocyclic Amine Esters (42) in asuitable mixture of THE and methanol, was added 1 M lithium hydroxidesolution (10–50 equivalents). When the N-terminal N-heterocyclic AmineEsters 42 was hydrolyzed to a satisfactory degree, the reaction mixturewas given an aqueous work up. The N-terminal N-heterocyclic Amine acid43 was purified chromatographically, except in cases where it was deemedunnecessary.

General Procedure for the Preparation of N-terminal N-heterocyclic AmineAmides 45

To a solution of the N-terminal N-heterocyclic Amine acid 43 in DMF, atroom temperature, was added NMM (20 equivalents). A suitably chosenamine hydrochloride (44) (20 equivalents) was added followed by DEPC (20equivalents). When the N-terminal N-heterocyclic Amine acid 43 wasconsumed to a satisfactory degree the N-terminal N-heterocyclic AmineAmide 45 was isolated either by direct chromatographic purification ofthe reaction mixture, or by an aqueous work up followed bychromatographic purification.

EXAMPLE 5

Preparation of Compounds 51 and 52

Step 1: Preparation of Compound 49:

Preparation of Compound 47:

Procedure a.

Compound 46 (1.0405 g, 4.4984 mmol) was dissolved in DMF (8.0 mL). K₂CO₃(0.6258 g, 4.5279 mmol) was added. Methyl iodide (0.6 mL, 9.6379 mmol)was added. The milky suspension was stirred at room temp under nitrogenfor 3 days. Standard aqueous workup yielded ester 47 as a colorless oil(1.0590 g, 96%).

Preparation of compound 2:

Compound 47 (0.9447 g, 3.8509 mmol) was dissolved in toluene (15 mL),and the solution was cooled to −78° C. under nitrogen. DIBAL (6.0 mL,6.00 mmol, 1.0 M in hexanes) was added via syringe over 5 min. Thesolution was stirred for 1 h, and was quenched with MeOH (1.0 mL) at−78° C. The bath was removed and 5.0 mL of saturated potassium sodiumtartrate solution was added. The mixture was stirred for ca. 1 h, andwas filtered through Celite. The filtrate was washed with H₂O and brine,and dried over Na₂SO₄, filtered, and evaporated to give compound 2(0.8413 g, 101%) sufficiently pure for the next step.

Preparation of Compound 3b:

Compound 2 (0.8413 g, 3.8509 mmol) was dissolved in CH₂Cl₂ (5.0 mL) and(carbethoxyethylidene)triphenylphosphorane (1.8212 g, 5.0254 mmol) wasadded. The solution was stirred at room temp under nitrogen overnight.The solution was evaporated, and the residue was diluted with EtOAc (70mL) and washed with H₂O (2×25 mL) and brine (25 mL), and dried overNa₂SO₄, filtered, and evaporated to give an oil. Purification by FlashChromatography on SiO₂ (FC) gave pure compound 3b (0.7863 g, 68%).

Preparation of Compound 48:

Compound 3b (0.7863 g, 2.6262 mmol) was dissolved in CH₂Cl₂ (1.0 mL) andtriethylsilane (0.460 mL, 2.880 mmol) was added. Trifluoroacetic acid(TFA) (2.5 mL) was added at room temp. After 30 min (complete reactionas judged by HPLC), the solution was evaporated to give a solid (1.1307g). This solid was dissolved in CH₃CN (ca. 10 mL) and 5.5 N HCl (2.4 mL,13.2 mmol) was added. Evaporation gave the HCl salt, compound 48 (0.618g, 100%).

Preparation of Compound 5b:

Compound 48 (0.390 g, 1.6543 mmol), L-N-BOC-t-butylglycine (1.0106 g,4.3694 mmol), CMC (1.9704 g, 4.6518 mmol), HOAt (0.5905 g, 4.3384 mmol),and NMM (0.490 mL, 4.4567 mmol) were combined, and DMF (4.0 mL) wasadded. The solution was stirred at room temp under nitrogen for 25 h.The solution was diluted with EtOAc (70 mL) and was washed with H₂O(2×25 mL), aq. pH 7.2 phosphate buffer (25 mL), H₂O (25 mL), and brine(25 mL), and dried over MgSO₄, filtered, and evaporated to give a solidwhich was purified by FC to give compound 5b (0.4239 g, 62%).

Preparation of Compound 49:

Compound 5b (0.1159 g, 0.2809 mmol) was dissolved in CH₂Cl₂ (3.0 mL) andtriethylsilane (0.050 mL, 0.3130 mmol) was added. Trifluoroacetic acid(TFA) (2.5 mL) was added at room temp. After 30 min (complete reactionas judged by HPLC), the solution was evaporated to give a solid. Thissolid was dissolved in CH₃CN (ca. 5 mL) and 5.5 N HCl was added (0.3 mL,1.65 mmol). Evaporation gave the HCl salt, compound 49 (0.0662 g, 100%).

Step 2: Preparation of Compound 51:

Preparation of Compound 50:

Compound 49 (0.0774 g, 0.2219 mmol), (R)-N-methylpipecolic (0.0705 g,0.3925 mmol), CMC (0.1752 g, 0.4136 mmol), HOAt (0.0344 g, 0.2527 mmol),and NMM (0.063 mL, 0.5730 mmol) were combined, and DMF (2.0 mL) wasadded. The solution was stirred at room temp under nitrogen for 20 h.The solution was purified directly by RP HPLC to give compound 50(0.0989 g, 81%).

Preparation of Compound 51:

Compound 50 (0.0989 g, 0.2086 mmol) was dissolved in 1:1H₂O/MeOH (14 mL)at room temp. LiOH (0.0537 g, 2.2422 mmol) was added. The suspension wasstirred at room temp. 19 h. The solution was acidified with 5.5 N HCl(0.50 mL), and purified by RP HPLC to give the TFA salt of 11 (0.0978 g,90%). This was dissolved in CH3CN (ca. 5 mL) and treated with 5.5 N HCl(ca. 1 mL, 5.5 mmol) and evaporated to give the HCl salt of compound 51(0.0667 g, 72%).

Step 2: Preparation of Compound 52:

Compound 51 (0.0062 g, 0.0139 mmol), L-proline methyl esterhydrochloride (0.0263 g, 0.1588 mmol) were dissolved in DMF (1.0 mL) atroom temp. under nitrogen. DEPC (0.017 mL, 0.1120 mmol) was added viasyringe. NMM (0.025 mL, 0.2274 mmol) was added via syringe. The solutionwas stirred overnight, quenched with H₂O (1.0 mL), and purified by RPHPLC to give the TFA salt of compound 52. This was dissolved in CH₃CN(ca. 3 mL) and treated with 5.5 N HCl (0.10 mL, 0.55 mmol) andevaporated to give the HCl salt of compound 52 (0.0078 g, 100%).

EXAMPLE 6

Preparation of Compound 62a

Preparation of Compound 54

To a solution of 4-methylpiperidine (53) (600 μL, 5.0 mmol) in MeOH (20mL) was added Et₃N (770 μL, 5.5 mmol) followed by Boc₂O (1.2 g, 5.5mmol) at 0° C. After 15 minutes, the reaction mixture was warmed to roomtemperature and allowed to stir overnight. The reaction solution wasthen diluted with H₂O and extracted several times with ether. The etherextracts were combined, dried over Mg₂SO₄, filtered, and concentrated toprovide compound 54 (926.5 mg) quantitatively as a colorless oil.

Preparation of Compound 55

A solution of compound 54 (926.5 mg, 5.0 mmol) in Et₂O (10.5 mL) wascooled to −78° C. and treated with TMEDA (755 μL, 5.0 mmol) followed byslow addition of a 1.3 M cyclohexane solution of sec-butyllithium (4.6mL, 6.0 mmol) over a 30 minute period. The reaction solution was thenwarmed to −20° C. and maintained at that temperature for 30 minutes,after which the solution was re-cooled to −78° C. and purged withgaseous carbon dioxide for 15 minutes. The reaction solution was thenslowly warmed to 0° C. and poured into a biphasic mixture of 1 N HCl(100 mL) and EtOAc (50 mL). The reaction solution was then extractedseveral times with EtOAc. The EtOAc extracts were combined, dried overMg₂SO₄, filtered, and concentrated to provide compound 55 (1.07 g) in89% yield as a colorless oil (a mixture of two cis enantiomers).

Preparation of Compound 59a

To a solution of compound 55 (292 mg, 1.2 mmol) in CH₂Cl₂ (2.4 mL) at 0°C. was added TFA (2.4 mL). After 15 minutes, the reaction solution waswarmed to r.t. and stirred for 3 hours. The reaction mixture was thenconcentrated in vacuo to provide compound 59a (309 mg) quantitatively asa light yellow oil.

Preparation of Compound 59b

Step 1: Preparation of Compound 56

To a solution of compound 55 (780 mg, 3.2 mmol) in DMF (6.4 mL) wasadded K₂CO₃ (663 mg, 4.8 mmol) followed by MeI (300 μL, 4.8 mmol). Thereaction solution was allowed to stir overnight. The reaction mixturewas then diluted with H₂O and extracted several times with ether. Theether extracts were combined, dried over Mg₂SO₄, filtered, andconcentrated in vacuo. Purification of the residue by silica gelchromatography (4% EtOAc in hexanes) yielded 535 mg (65%) of compound 56as a colorless oil.

Step 2: Preparation of Compound 57

To a solution of compound 56 (463 mg, 1.8 mmol) in MeOH (2.6 mL) wasadded a 25 wt % solution of NaOMe in MeOH (100 μL). The solution wasallowed to stir overnight. The reaction mixture was then diluted withH₂O and extracted several times with ether. The ether extracts werecombined, dried over Mg₂SO₄, filtered, and concentrated in vacuo.Purification of the residue by silica gel chromatography (4% EtOAc inhexanes) yielded 363.6 mg (79%) of racemic compound 57 as a colorlessoil.

Step 3: Preparation of Compound 58

To a solution of compound 57 (360 mg, 1.4 mmol) in a 2:1 mixture of H₂O(2.75 mL) and EtOH (5.50 mL) was added KOH pellets (786 mg, 14 mmol) andthe reaction solution was stirred at room temperature until complete byTLC. The reaction mixture was then diluted with H₂O and extractedseveral times with ether. The ether extracts were combined, dried overMg₂SO₄, filtered, and concentrated to provide compound 58 (341 mg)quantitatively as a white solid.

Step 4: Preparation of Compound 59b

To a solution of compound 58 (292 mg, 1.2 mmol) in CH₂Cl₂ (2.4 μL) at 0°C. was added TFA (2.4 mL). After 15 minutes, the reaction solution waswarmed to r.t. and stirred for 3 hours. The reaction mixture was thenconcentrated in vacuo to provide compound 59b (309 mg) quantitatively asa light yellow oil.

Preparation of Compounds 60a and 60b

To a solution of compound 59a (or 59b) (283 mg, 1.1 mmol) in MeOH (5 mL)was added Pd(OH)₂ (75 mg) followed by a 37 wt % solution of formaldehydein H₂O (300 μL). Gaseous H₂ (balloon pressure) was charged in and thereaction mixture was allowed to stir under an H₂ atmosphere overnight.The reaction solution was then filtered through a bed of celite, andconcentrated to provide compound 60a (or 60b) (173 mg) quantitatively asa white solid.

Preparation of Compounds 61a and 61b

To a solution of compound 60a and 60b (11.0 mg, 0.07 mmol) in CH₂Cl₂(350 μL) was added HBTU (40 mg, 0.11 mmol) and DIEA (37 μL, 0.21 mmol).After 5 minutes, amine 49 (22.0 mg, 0.07 mmol) was added. The reactionmixture was stirred for 30 minutes, filtered, and concentrated.Purification of the residue by silica gel chromatography (2% EtOH inCH₂Cl₂) yielded 15.1 mg (96%) of each diastereomer 61a and 61b ascolorless oils.

Preparation of Compound 62a

To a solution of diastereomer 61a (9.0 mg, 0.02 mmol) in a 2:1 mixtureof H₂O (0 μL) and EtOH (160 μL) was added LiOH, H₂O (840 mg, 0.20mmols). The reaction solution was allowed to stir overnight. Thereaction mixture was then acidified with 1 N HCl until the pH=6.00. Thesolution was then extracted several times with CH₂Cl₂. The CH₂Cl₂extracts were combined, dried over Mg₂SO₄, filtered, and concentrated toprovide compound 62a (8.4 mg) quantitatively as a white solid.

EXAMPLE 7

Preparation of Compound 67b

Preparation of Compound 64

To a suspension of L-penicillamine (63) (300 mg, 2.0 mmol) in methanol(10 mL) was added benzaldehyde (233 mg, 2.2 mmol) followed by sodiumbicarbonate (336 mg, 4.0 mmol). The mixture was heated to reflux withstirring for 16 h. After cooling to r.t., it was acidified to pH 5 with1 N HCl and extracted with ethyl acetate three times. The organic phasewas concentrated to give a yellow solid as the crude product 64 (469 mg,99%)

Preparation of Compound 65

To a solution of crude 64 (47 mg, 0.2 mmol) in THF (1 mL) was added aq.37% formaldehyde solution (49 μl, 0.6 mmol) followed by NaBH₄ (38 mg,0.6 mmol). The mixture was stirred at r.t. for 24 h. After acidifying topH 5 and extracting with ethyl acetate, the organic phase was dried andconcentrated to give crude product 65 (67 mg, >100%).

Preparation of Compounds 66a and 66b

To a mixture of 65 (29 mg, 0.115 mmol), amine HCl salt 49 (15 mg, 0.043mmol), CMC (55 mg, 0.129 mmol), and HOAt (3 mg, 0.022 mmol) was addedDMF (0.5 mL) followed by NMM (6 ml, 0.055 mmol). The mixture was stirredat r.t. for 24 h. The reaction was quenched by adding water (0.5 mL) andmethanol (0.5 mL). The products 66a (32%), and 66b (75%) were obtainedafter separation by RP HPLC (0–100% B in 30 min. A: 5% MeCN+0.15% TFA inH₂O; B: 0.15% TFA in MeCN) and lyophilization.

Preparation of Compounds 67b

To a solution of 66b (4 mg, 0.0073 mmol) in methanol (0.5 mL) was addedaq. LiOH (1 M, 0.5 mL). The mixture was stirred for 16 h and acidifiedwith 1 N HCl. Product 67b (2.79 mg, 74%) was obtained after RP HPLCpurification and lyophilization.

EXAMPLE 8

Preparation of Compound 74

Preparation of Compound 69

To a solution of diethylglycine (68) (131 mg, 1.0 mmol) in 1 N NaOH (1.5mL) was added a solution of di-t-butyl-dicarbonate (436 mg, 2.0 mmol) indioxane (1.0 mL). The mixture was stirred for 16 h. It was acidified topH 3 with 1 N HCl and extracted with ethyl acetate three times. Theorganic phases were combined, dried, and concentrated to yield crudeproduct 69 (135 mg, 58%).

Preparation of Compound 70

To a solution of crude 69 (135 mg, 0.58 mmol) in MeOH (0.5 mL) and THF(0.5 mL) was added trimethylsilyldiazomethane (2 M in hexanes, 2.0mmol). The solution was stirred at r.t. for 1 h. Evaporation gave crudeproduct 70 (0.58 mmol).

Preparation of Compound 71

To a mixture of sodium hydride (160 mg 60%, 4 mmol) in DMF (1 mL) wasadded a solution of compound 70 (0.58 mmol) in DMF (1 mL) followed bymethyl iodide (188 μl, 3 mmol). The mixture was stirred at roomtemperature for 24 h. Water was added to quench the reaction. Theproduct 71 (118 mg, 78% 2 steps) was extracted with ethyl acetate andpurified by flash column chromatography (silica, ethyl acetate/exanes).

Preparation of Compound 72

A solution of compound 71 (118 mg, 0.46 mmol) in conc. HCl (1 mL) wasstirred at room temp. for 24 h. Product 72 was obtained afterevaporation of volatiles.

Preparation of Compound 73

To a mixture of compound 72 (30 mg, 0.166 mmol), amine 49 HCl salt (39mg, 0.166 mmol), CMC (141 mg, 0.332 mmol), and HOAt (14 mg, 0.103 mmol)was added DMF (1.5 mL) followed by NMM (6 ml, 0.128 mmol). The mixturewas stirred at room temp. for 24 h. The reaction was quenched by addingwater (0.5 mL) and methanol (0.5 mL). Product 73 (27 mg, 34%) wasobtained after separation by RP HPLC (0–100% B in 30 min. A: 5%MeCN+0.15% TFA in H₂O; B: 0.15% TFA in MeCN) and lyophilization.

Preparation of Compound 74

To a solution of compound 73 (18 mg) in methanol (0.5 mL) was added aq.LiOH (1 M, 0.5 mL). The mixture was stirred for 16 h and then acidifiedby 1 N HCl. Product 74 (12.3 mg, 73%) was obtained after RP HPLCpurification and lyophilization.

EXAMPLE 9

Preparation of Compound 78

Preparation of Compound 76

To a solution of compound 75 (123 mg) in dry DCM (1 mL), at 0° C. underan inert atmosphere, was added a 1 M solution of DIBAL (1.6 mL)dropwise. The reaction mixture was stirred at 0° C. for 2 hr thenallowed to warm to 10° C. then re-cooled to 0° C. Methanol (0.22 mL) wasadded dropwise followed by a saturated solution of ammonium chloride(0.44 mL). DCM (20 mL) was added and the reaction mixture stirredvigorously at room temperature for 30 min. Filtration followed byconcentrated in vacuo gave compound 76 (73 mg, 65%).

Preparation of Compound 77

To a solution of compound 76 (3 mg) in acetonitrile (0.6 mL) was addedDess Martin periodinane (3.1 mg). The reaction mixture was stirred atroom temperature for 1 hr then diluted with diethyl ether (2 mL). Theresultant suspension was filtered through a 0.25 μm PTFE syringe filterand concentrated in vacuo to give crude compound 77 (4 mg).

Preparation of Compound 78

To a solution of compound 77 (3 mg) in DCM (0.5 mL), at roomtemperature, was added ethyl carbethoxymethylidene triphenylphosphorane(21 mg). The reaction mixture was stirred at room temperature for 16 hrthen concentrated in vacuo to dryness. Chromatographic purification gavecompound 78 (1.48 mg, 44%).

EXAMPLE 10

Preparation of Compound 81

Preparation of Compound 79

To a solution of compound 7b (10 mg) in dry DCM (0.5 in mL), at 0° C.under an inert atmosphere, was added a 1 M solution of DIBAL (0.085 mL)dropwise. The reaction mixture was stirred at 0° C. for 1.5 hr thenmethanol (0.012 mL) was added dropwise followed by a saturated solutionof ammonium chloride (0.024 mL). DCM (5 mL) was added and the reactionmixture stirred vigorously at room temperature for 20 min. Filtrationfollowed by concentrated in vacuo gave crude compound 79 (9 mg, 95%).

Preparation of Compound 80

To a solution of compound 79 (5 mg) in THF (0.5 mL) was added sodiumbicarbonate (3.6 mg) and Dess Martin periodinane (7.2 mg). The reactionmixture was stirred at room temperature for 3 hr then concentrated invacuo to give crude compound 80.

Preparation of Compound 81

To a solution of compound 80 (4.8 mg) in ethanol (0.5 mL), at roomtemperature, was added hydroxylamine hydrochloride (4 mg) and sodiumacetate (6 mg). The reaction mixture was stirred at 40° C. for 1.5 hrthen concentrated to dryness. The residue was dissolved in DCM (0.2 mL)and treated with TFA (0.2 mL) and stood at room temperature for 10 min.Concentration in vacuo to dryness followed by chromatographicpurification gave compound 81 (2.04 mg).

EXAMPLE 11

Preparation of Compound 87

Preparation of Compound 84

To a solution of compound 28 (335 mg) in THF (10 mL), at 0° C. under aninert atmosphere, was added sodium hydride (65% dispersion in mineraloil; 144 mg) portionwise. The reaction mixture was stirred at 0° C. for30 min then treated with methyl iodide (0.405 mL). The reaction mixturewas allowed to warm to room temperature and stirred at room temperaturefor 3 hr. An aqueous work up followed by chromatographic purificationgave compound 84 (254 mg, 72%).

Preparation of Compound 85

Compound 84 (189 mg) was treated with saturated HCl in methanol (5 mL).The reaction mixture was stood at room temperature for 2 hr thenconcentrated in vacuo to dryness to give compound 85 (145 mg).

Preparation of Compound 86

To a solution of compound 85 (145 mg) in DMF (3 mL), at roomtemperature, was added (S)-N-Boc-tert-leucine (483 mg), NMM (0.230 mL),HOAt (95 mg), and CMC (884 mg). The reaction mixture was shaken at roomtemperature for 16 hr. Aqueous workup followed by chromatographicpurification gave an intermediate Boc compound (249 mg, 93%). Theintermediate Boc compound (60 mg) was dissolved in methanol (1 mL) andtreated with saturated HCl in methanol (3 mL) and stood at roomtemperature for 30 min. Concentration in vacuo gave compound 86 (49 mg).

Preparation of Compound 87

To a solution of compound 86 (49 mg) in DMF (0.44 mL), at roomtemperature, was added (S)-N-Boc-neo-phenylalanine (94 mg), NMM (34 μl),HOAt (21 mg), and CMC (130 mg). The reaction mixture was shaken at roomtemperature for 16 hr. Aqueous workup followed by chromatographicpurification gave an intermediate Boc compound (41 mg, 47%). Theintermediate Boc compound (5.5 mg) was dissolved in DCM (1 mL) andtreated with TFA (1 mL). The reaction mixture was stood at roomtemperature for 30 min then concentrated in vacuo to dryness. Theresidue was dissolved in saturated HCl in methanol (1 mL) and stood atroom temperature and then concentrated in vacuo to give compound 87(4.39 mg, 89%).

EXAMPLE 12

Preparation of Compound 91

Preparation of Compound 88

To a solution of compound 28 (344 mg) in 0.5 M Hunnig's base in DCM (8mL), at 0° C. under an inert atmosphere, was added methane sulphonylchloride (0.207 mL) dropwise. The reaction mixture was stirred at 0° C.for 1.5 hr then subjected to an aqueous work up followed bychromatographic purification to give an intermediate mesylate (444 mg).The intermediate mesylate was dissolved in DMSO (2 mL) and treated withsodium azide (258 mg). The reaction mixture was heated at 40° C. for 6hr. An aqueous work up gave compound 88 (306 mg, 82%).

Preparation of Compound 89

Compound 88 (140 mg) was dissolved in DCM (1 mL) and treated with TFA (1mL). The reaction mixture was stood at room temperature for 30 min thenconcentrated in vacuo to dryness. The residue was dissolved in saturatedHCl in methanol (1 mL) and stood at room temperature and thenconcentrated in vacuo to give compound 89 (109 mg).

Preparation of Compound 90

To a solution of compound 89 (109 mg) in DMF (2 mL), at roomtemperature, was added (S)-N-Boc-tert-leucine (347 mg), NMM (0.165 mL),HOAt (68 mg) and CMC (635 mg). The reaction mixture was stirred at roomtemperature for 16 hr. Aqueous workup followed by chromatographicpurification gave an intermediate Boc compound (173 mg, 87%). Theintermediate Boc compound (51 mg) was dissolved in methanol (1 mL) andtreated with saturated HCl in methanol (3 mL) and stood at roomtemperature for 30 min. Concentration in vacuo gave compound 90 (43 mg).

Preparation of Compound 91

To a solution of compound 90 (42 mg) in DMF (0.37 mL), at roomtemperature, was added (S)-N-Boc-neo-phenylalanine (79 mg), NMM (28 μl),HOAt (17 mg), and CMC (108 mg). The reaction mixture was shaken at roomtemperature for 16 hr. Aqueous workup followed by chromatographicpurification gave an intermediate Boc compound (88 mg). The intermediateBoc compound (88 mg) was dissolved in saturated HCl in methanol (5 mL)and stood at room temperature for 30 min and then concentrated in vacuoto give compound 91 (70 mg, 89%).

EXAMPLE 13

General Procedure for the Preparation of C-terminal Acid Compounds

To a solution of the corresponding methyl or ethyl ester (e.g., compound7b) in a suitable mixture of methanol and tetrahydrofuran, at roomtemperature, was added aqueous 1 M lithium hydroxide (10–50equivalents). The reaction mixture was stirred or shaken or stood atroom temperature until the starling ester had been satisfactorilyhydrolyzed. The usual workup followed by chromatographic purificationgave the desired C-terminal acid compound (e.g., compound 82).

EXAMPLE 14

Preparation of Compound ER-807974

Preparation of Compound ER-807641

To a stirred solution of N-Boc-N-Me-L-Valine (200 g, 0.86 mols),N,O-demethylhydroxylamine (92.8 g, 0.95 mols, 1.1 eq) and DIEA (316.3mL, 1.82 mol, 2.1 eq) in CH₃CN (2 L) at 0° C. was added HBTU (360.7 g,0.95 mols, 1.1 eq) in portions. The solution was stirred at 0° C. foradditional 15 min and then for 1 h at 25° C. Reaction was monitored byTLC (Hept./EtOAc 1:1) and deemed completed when no 46 was observed. Thesolution was concentrated by rota-vap and then diluted in TBME (1 L).The organic solution was washed with HCl (1N, 500 mL), water (250 mL),NaHCO₃ (sat. 250 mL) and brine (250 mL). The organic solution was driedover MgSO₄ (˜120 g). The solution was filtered through a silica gel bed(˜200 g) and concentrated. Crude amide ER-807641 was used without anyfurther purification.

Preparation of Compound ER-808993

To a stirred solution of amide ER-807641 (207 g, 755 mmol, 1 eq.) in dryTHF (2070 mL) at −78° C. was added a solution of LiAlH₄ (1.0M/THF, 754mL, 755 mmol, 1.0 eq.). The solution was stirred at −78° C. for 1 h.Reaction was quenched at −78° C. by addition of reaction solution to asuspension of Na₂SO₄. 10H₂O (243 g) in TBME (1.5 L). The slurry wasallowed to warm up to ˜15° C. and was then filtered through a Celitepad. The filtrate was concentrated, and the crude aldehyde ER-808993 wasobtained as a clear oil and used without further purification.: 157.9 g(97%).

Preparation of Compound ER-808995-01

Part A:

To a stirred solution of aldehyde ER-808993 (138 g, 641 mmol, 1 eq.) indry THF (1.4 L) at 25° C. was added Ph₃P═CMeCO₂Et (256 g, 705.1 mmol,1.1 eq.). The solution was stirred at r.t for 18 h. Reaction was notcompleted after that time. The solution was heated to reflux for 5 h,after which TLC showed no aldehyde remaining. The solution was cooled toroom temp and heptane (1.5 L) was added. Precipitation of by-productPh₃P═O was observed. The mixture was filtered through a silica gel (200g) plug. The filtrate was concentrated to a minimum volume (50 mL), andthe residue was dissolved in EtOAc (800 mL).

Part B:

To a stirred solution of crude ER-808994 in EtOAc (800 mL) was added MSA(80 mL). The mixture was stirred at r.t. for 45 min. (until complete byTLC). The amino-ester MSA salt was extracted from organic solution withwater (2×300 mL). The aqueous layer was neutralized to pH 7–8 with sat.NaHCO₃ (300 mL). The resultant solution was extracted with EtOAc (2×400mL), washed with brine (300 mL), dried over MgSO₄, and filtered. TheEtOAc solution of the free amino-ester was bubbled with HCl (gas), andthe HCl salt of ER-808995 precipitated and was collected by filtrationunder N₂.

Preparation of Compound ER-803921-01

To a stirred solution of ER-808995 (61.2 g, 259.6 mmol, 1 eq.),N-Boc-tBu-Gly-OH (90.1 g, 389.4 mmol, 1.5 eq) and DIEA (158 mL, 906.6mmol, 3.5 eq) in dry DCM (612 mL) at 25° C. was added HBTU (147.7 g,389.4 mmol, 1.5 eq.). The solution was stirred at room temp for 4 hAfter concentration, the solid residue was suspended in TBME (250 mL).The mixture was filtered through a silica gel bed (˜120 g), and thefiltrate was washed with a solution of aq. HCl (1N, 200 mL), water (200mL) and NaHCO₃ (sat, 200 mL). The organic layer was dried over MgSO₄,filtered and concentrated. The N-Boc-amino-ester ER-808996 was isolatedas an oil. This intermediate was re-dissolved in EtOAc (120 mL) and MSA(75 mL) was added. The solution was stirred at room temp for 1 h, atwhich time the reaction was deemed complete by TLC. The amino-ester MSAsalt was extracted with water (2×250 mL), followed by neutralizationwith a solution NaOH (ca. 50%, 300 mL) to pH˜8–9. The free amine wasextracted with TBME (2×30 mL). The combined organic solution was washedwith water (200 mL) and brine (200 mL). After drying over MgSO₄ andfiltration, HCl (g) was bubbled to obtain the hydrochloride salt ofER-803921 as a white solid collected by filtration at ca. 5° C.

Preparation of Compound ER-808998

A stirred suspension of D-pipecolic acid (100.0 g, 0.77 mol, 1 eq.) andPd(OH)₂ (20% wt. Pd, 10 g) in a mixture MeOH/acetone (2:1 v/v, 1.5 L)was submitted to hydrogenation (H₂ 60 psi) for 24 h. Reaction wasmonitored by TLC (ethanol) and deemed complete when no D-pipecolic acidwas observed. The mixture was filtered through a Celite (˜50 g) bed. Theclear filtrate was concentrated to ca. 100 mL and TBME (50 mL) wasadded. ER-808998 was filtered as a white crystalline solid in 88% yield.

Preparation of Compound ER-807961

To a stirred solution of dipeptide ER-803921 (5.0 g, 16.8 mmol, 1 eq.),N-iPr-pipecolic acid ER-808998 (3.7 g, 21.8 mmols, 1.3 eq.) and HBTU(8.3 g, 21.8 mmols, 1.3 eq.) in 50 mL DCM was added DIEA (7.3 mL, 41.9mmols, 2.5 eq.) dropwise at 25° C. The mixture was stirred for 18 h(overnight) at which time reaction was deemed complete by TLC(heptane/EtOAc 1:1). The mixture was concentrated under vacuum and TBME(50 mL) was added. The residual “thick” oil was separated from theethereal solution by filtration through a Celite pad. The filtrate waswashed with aq HCl (1M, 3×25 mL). The combined aqueous phases wereneutralized with NH₄OH to pH 8–9 in the presence of EtOAc (25 mL). Theaqueous layer was separated and back-extracted with TBME (25 mL). Thecombined organic phase was washed with brine and dried over MgSO₄,filtered, and concentrated to give tripeptide-amino-ester ER-807961 in93% yield.

Preparation of Compound ER-807974

To a stirred solution of ester ER-807961 (5.0 g, 16.8 mmol) in 5:1THF/H₂O (50 mL) was added LiOH (3.50 g, 83.8 mmol), and the mixture wasstirred at room temperature for 20 h. The reaction was monitored by TLC(ethanol) and deemed complete when no ER-807961 was observed. Thesuspension was acidified with H₂SO₄ (˜0.50 mL) to pH 7. The mixture wasextracted with EtOAc (3×25 mL). The combined organic solution was washedwith brine (20 mL), dried over MgSO₄, filtered, and concentrated. Theresidue was triturated with TBME: 1.8 g (83%) of thick oil free-baseER-807974 was obtained.

EXAMPLE 15

Preparation of Compound ER-808367

Preparation of Compound 2Z

To a suspension of D-pipecolic acid 1Z (750 mg, 5.81 mmol) in MeOH (23.2mL) and 2-butanone (11.6 mL) was added Pd(OH)₂ (175 mg). Gaseous H₂(balloon pressure) was charged in and the reaction mixture was allowedto stir under an H₂ atmosphere overnight. The reaction solution was thenfiltered through a bed of celite, and concentrated to give a crude whitesolid. The crude product was subjected to flash chromatography (SiO₂)eluting with 100% EtOH. This provided compound 2Z (721 mg, white solid)as a mixture of diastereomers in 67% yield.

Preparation of Compounds 3Z and 4Z

To a solution of 2Z (650 mg, 3.51 mmol) in DMF (8.8 mL) was added K₂CO₃(728 mg 5.27 mmol) and p-nitrobenzylbromide (1.1 g 5.27 mmol). Thereaction mixture was allowed to stir overnight. The reaction solutionwas diluted with water and extracted several times with diethyl ether.The ether extracts were combined, washed with water and brine. Thesolution was dried over MgSO₄, filtered, and concentrated in vacuo. Thecrude mixture of diasteomers was then separated by flash chromatographyeluting with 8% EtOAc in hexanes to give each diastereomer as a paleyellow oil. Compound 3Z (360 mg) was obtained in 32% yield with anR_(f)=0.590 (SiO₂) using 30% EtOAc in hexanes. Compound 4Z (652 mg) wasobtained in 58% yield with an R_(f)=0.482 (SiO₂) using 30% EtOAc inhexanes.

Preparation of Compound ER-809439

To a solution of compound 3Z (320 mg, 1.0 mmol) in MeOH (10 mL) wasadded Pd(OH)₂ (50 mg). Gaseous H₂ (balloon pressure) was charged in andthe reaction mixture was allowed to stir under an H₂ atmosphere for 3hours. The reaction solution was then filtered through a bed of celite,and concentrated to provide compound ER-809439 (185 mg) as a whitesolid, quantitatively. Compound ER-809439, R_(f)=(SiO₂, 0.292, 100%EtOH).

Preparation of Compound ER-809447

A procedure similar to that used for the preparation of compoundER-809439 was used. Compound ER-809447, R_(f)=(SiO₂, 0.292, 100% EtOH).

Preparation of Compound ER-808357

Compound 49 (9.6 mg, 0.031 mmol), N-sec-butylpipecolic ER-809439 (5.2mg, 0.028 mmol), HBTU (12.9 mg, 0.034 mmol), were combined. DMF (0.28mL) was added, followed by DIEA (14.9 mL, 0.084 mmol). The solution wasstirred at room temperature under nitrogen for 20 h. The solution waspurified directly by RP HPLC to give the TFA salt of compound ER-808357(13.6 mg, 82%).

Preparation of Compound ER-808367

The TFA salt of compound ER-088357 (10.4 mg, 0.018 mmol) was dissolvedin 1:2H₂O/EtOH (0.072 mL/0.144 mL) at room temperature. LiOH (7.5 g,0.18 mmol) was added. The suspension was stirred at room temperature for19 hours. The solution was purified directly by RP HPLC to give the TFAsalt of compound ER-808367 (10.1 mg, quantitative).

EXAMPLE 16

Preparation of Compound ER-808368

Preparation of Compound ER-808358

A procedure similar to that used for the preparation of compoundER-808357 was used.

Preparation of Compound ER-808368

A procedure similar to that used for the preparation of compoundER-808367 was used.

EXAMPLE 17

Preparation of Compound ER-808662

Preparation of Compound 5Z

To a suspension of D-pipecolic acid 1Z (1.00 g, 7.74 mmol) in MeOH (31mL) and 3-methyl-2-butanone (15.5 mL) was added Et₃N (1.1 mL) andPd(OH)₂ (250 mg). Gaseous H₂ (balloon pressure) was charged in and thereaction mixture was allowed to stir under an H₂ atmosphere overnight.The reaction solution was then filtered through a bed of celite, andconcentrated to give a crude white solid. The crude product wassubjected to flash chromatography (SiO₂) eluting with 100% EtOH. Thisprovided compound 5Z (377.9 mg, white solid) as a single diastereomer in24.5% yield. R_(f)=(SiO₂, 0.280, 100% EtOH).

Preparation of Compound ER-808656

A procedure similar to that used for the preparation of compoundER-808357 was used.

Preparation of Compound ER-808662

A procedure similar to that used for the preparation of compoundER-808367 was used.

Compounds ER-809638 through ER-809650 were made according to theprocedures for ER-808368 or ER-808662 with the one change:N-BOC-L-Valine was used in place of N-BOC-N-Methyl-L-Valine (46).Compounds ER-808998, ER-809439 and 5Z were used as required.

EXAMPLE 18

Preparation of Compound ER-808824

Preparation of Compound 6Z

Compound 48 (325.5 mg, 1.38 mmol), L-N-BOC-valine (300.0 mg, 1.3S mmol),HBTU (628.3 mg, 1.66 mmol), were combined. CH₂Cl₂ (7 mL) was added,followed by DIEA (0.72 mL, 4.14 mmol). The solution was stirred at roomtemperature under nitrogen for 1 hour. The solution was concentrated invacuo, and the crude was purified by flash chromatography (SiO₂) elutingwith 4% EtOAc in hexanes. This provided compound 6Z (476.8 mg) as acolorless oil in 86.7% yield.

Preparation of Compound 7Z

Compound 6Z (450 mg, 1.13 mmol) was dissolved directly in 4N HCl/dioxane(2.8 mL). The reaction was stirred for overnight and then concentratedin vacuo to give compound 7Z (374.5 mg) as a white solid,quantitatively.

Preparation of Compound ER-808815

A procedure similar to that used for the preparation of compoundER-808357 was used.

Preparation of Compound ER-808824

A procedure similar to that used for the preparation of compoundER-808367 was used.

EXAMPLE 19 Biological Assays

In certain embodiments, compounds of the invention were tested for invitro and in vivo activity. Screening methods included standard in vitrocell growth inhibition assays using a panel of human cancer cell lines,a U937 (ATCC accession number CRL 1593) mitotic block reversibilityassay, mouse serum stability assay, MDR assay, and cytotoxicity assay.In certain other emdodiments, compounds of the invention were evaluatedin tumor xenograft in vivo growth inhibition assays.

In vitro potency was determined in the MDA-MB-435 cell growth inhibitionassay, and active compounds (IC₅₀<20 nM) were evaluated in thereversibility, MDR, and mouse serum stability assays. In addition, theactive compounds were tested in the IMR-90 cytotoxicity assay and inadditional cell growth inhibition assays in a panel of human cancer celllines, both solid and non-solid tumors.

Cell growth inhibition assay: Cultured human cancer cells (includingbreast, prostate, colon, lung, leukemia, lymphoma and other) were platedin 96-well plates and grown in the continuous presence of test compoundsfor 72 or 96 hours. The human cell lines used in this cell growthinhibition assay, include, but are not limited to, the following solidtumor cell lines and non-solid tumor cell lines: DLD-1 colon cancercells (ATCC accession number CCL-221), DU 145 prostate cancer cells(ATCC accession number HTB-81), H460 non small cell lung cancer, HCT-15colon cancer cells (ATCC accession number CCL-225), HEL erythroleukemiacells, HL-60 promyelocytic leukemia cells (ATCC accession numberCCL-240), K562 leukemia (ATCC accession number CCL-243), LOX melanoma,MDA-MB-435 breast cancer cells, U937 lymphoma cells (ATCC accessionnumber CRL 1593), PANC-1 pancreatic cancer (ATCC accession numberCRL-1469), HCC-2998 colon cancer (NCI-Frederick Cancer DCTD Tumor/CellLine Repository), HCT 116 colon cancer (ATCC accession number CCL-247),HT-29 colon cancer (ATCC accession number HTB-38), LoVo colon cancer(ATCC accession number CCL-229), SW-480 colon cancer (ATCC accessionnumber CCL-228), SW-620 colon cancer (ATCC accession number CCL-227) andCOLO-205 colon cancer (ATCC accession number CCL-222). For monolayercultures, growth was assessed using modifications (Amin et al, CancerRes., 47: 6040–6045, 1987) of a methylene blue-based microculture assay(Finlay et al, Anal. Biochem., 139: 272–277, 19S4). Absorbances at 620and 405 nm were measured on a Titertek Multiscan MCC/340 plate readerand absorbances at 405 nm were subtracted from absorbances at 620 nm.For suspension cultures, growth was assessed using a3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide-basedassay (Mosmann et al, J. Immunol. Methods, 65: 55–63, 1983) modified asfollows. After 4 days of incubation with test compounds,sterile-filtered 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazoliumbromide was added to each well (final concentration, 0.5 mg/ml), andplates were incubated at 37° C. for 4 h. Acid-isopropanol (0.1 N HCl inisopropanol, 150 mL) was then added to each well, and the resultantformazan crystals were dis-solved by gentle mixing. Absorbances at 540nm were measured on a Titertek Multiscan MCC/340 plate reader.

Mitotic block reversibility assay was performed as described (See, U.S.Pat. No. 6,214,865 B1, by B. Littelfield et al, Apr. 10, 2001; which isincorporated herein be reference in its entirety).

Briefly, U937 (ATCC accession number CRP 1593) were exposed to variousconcentration of compounds for 12 hours. The compounds were washed awayand the cells were allowed to recover for an additional 10 hours. Thecells were collected by centrifugation and fixed overnight in 70%ethanol. The cells were washed in PBS, incubated with RNase A andstained with propidium iodide. Single channel flow cytometry wasperformed on a Becton Dickinson FACScan; the collection and analysis ofdata were performed using Becton Dickinson CELLQuest software. Doubletevents were eliminated from analyses by proper gating on FL2-W/FL2-Aprimary plots before histogram analysis of DNA content (measured asFL2-A).

Determination of activity in vitro utilizing the MDR assay. This is amodification of the standard cell growth inhibition assays describedabove. Two cultured human cancer cell lines were used: human uterinesarcoma MDR negative MES-SA cells (ATCC accession number CRL-1976) andhuman uterine sarcoma MDR-positive MES-SA/Dx5 cells (ATCC accessionnumber CRL-1977). Cells were plated in a 96-well microtiter plates at adensity of 7500 cells/well. The cells were incubated in the presence orabsence of test compounds for 96 hours. Cell growth was assessed usingmodifications (Amin et al, Cancer Res., 47: 6040–6045, 1987) of amethylene blue-based microculture assay (Finlay et al, Anal. Biochem.,139: 272–277, 1984). Absorbances at 620 and 405 nm were measured on aTitertek Multiscan MCC/340 plate reader and absorbances at 405 nm weresubtracted from absorbances at 620 nm. The ratio of the concentrationsof the compounds inhibiting the growth of cells by 50% was calculatedand used to estimate the sensitivity of the compounds to MDR(multidrug-resistance, or P-glycoprotein-mediated drug efflux). In somecases, a different pair of cell lines was used: MDR-negative murineleukemia cells P388/S, and MDR-positive murine leukemia cellsP388/VMDRC.04. Cells were plated in a 96-well microtiter plates at adensity of 4000 cells/well. The cells were incubated in the presence orabsence of test compounds for 72 hours. Cell growth was assessed using a3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide-basedassay (Mosmann et al, J. Immunol. Methods, 65: 55–63, 1983) modified asfollows. After 3 days of incubation with test compounds,sterile-filtered 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazoliumbromide was added to each well (final concentration, 0.5 mg/ml), andplates were incubated at 37° C. for 4 h. Acid-isopropanol (0.1 N HCl inisopropanol, 150 mL) was then added to each well, and the resultantformazan crystals were dis-solved by gentle mixing. Absorbances at 540nm were measured on a Titertek Multiscan MCC/340 plate reader.

Stability to esterase degradation was determined in the mouse serumstability assays. The enzymatic activity of mouse serum can result ininactivation of compounds in vivo despite their promising in vitroactivity. A modification of the standard cell growth inhibition assaysdescribed above was used to determine stability of the test compounds toesterase degradation. Human breast carcinoma cell line MDA-MB-435 orhuman prostate carcinoma cell line DU 145 were used. The cells wereplated in a 96-well microtiter plates at a density of 7500 cells/well.Prior to adding the test compounds to cells in the cell growthinhibition assay, the test compounds were incubated in 100% mouse serumor normal growth medium for 6 hours at 37° C. After that, the testcompounds were added to the 96-well microtiter plates containing thecells. The cells were incubated in the presence or absence of testcompounds for 96 hours. Cell growth was assessed using modifications(Amin et al, Cancer Res., 47: 6040–6045, 1987) of a methylene blue-basedmicroculture assay (Finlay et al, Anal. Biochem., 139: 272–277, 1984).Absorbances at 620 and 405 nm were measured on a Titertek MultiscanMCC/340. Ability of test compounds to inhibit cell growth aftercompounds' exposure to mouse serum esterases was assessed.

Cytotoxicity assay. To determine toxicity of compounds against normal,non-dividing cells, quiescent IMR-90 normal human fibroblasts (ATCCaccession number CCL-186) were used. IMR-90 cells were plated in a96-well microtiter plate format and grown to confluency (for 72 hours).After the 72-hour growth, the cells were washed and the medium wasreplaced from normal medium containing 10% fetal bovine serum to mediumcontaining low concentration of serum (0.1%). Cells were made quiescentby incubation in 0.1% serum-containing growth medium for additional 72hours. Cells were incubated with the test compounds for 24 hours.Cellular ATP levels were measured using a ViaLight HS kit (LumiTechLtd). A cytotoxic compound carbonyl cyanide was used in all assays as apositive control for cytotoxicity.

Determination of antitumor activity in vivo in mice. In vivo tumorxenograft studies were performed in immunocompromised (nude) mice. Mice(female Ncr athymic) were implanted subcutaneously with human tumorxenografts (including breast MDA-MB-435, colon COLO-205, HCT-15,HCT-116, HCC-2998, HT-29. SW-620, DLD-1, LoVo, melanoma LOX, lung H522,pancreatic PANC-1). After the xenografts reached an average size of75–200 mm³ or 400–600 mm³, the animals were weighed and randomly dividedinto groups of 8–10 on the first day of compound administration. Testcompounds were administered intravenously or intraperitoneally. Tumorand body weight measurements were done twice weekly.

1. A compound having the structure (I):

or pharmaceutically acceptable salt thereof; wherein n is 1; X₁ and X₂are each C(═O); the moiety having the structure

forms a piperidine moiety having the structure

wherein g, j, l and m are each 1; each occurrence of G, J, L and M isindependently CHR^(iv), or CR^(iv)R^(v), wherein each occurrence ofR^(iv) and R^(v) is independently hydrogen, or an aliphatic, alicyclic,or aryl moiety; R₂ is hydrogen, or optionally substituted alkyl orarylalkyl; where the alkyl moiety is linear or branched, cyclic oracyclic; R₃ is hydrogen; R₅, R₆ and R₇ are each independently hydrogenor substituted or unsubstituted, linear or breached, cyclic or acyclicalkyl; R is —CH(R_(8a))C(R_(9a))═C(R_(10a))—; where R_(8a) issubstituted or unsubstituted, linear or branched, cyclic or acyclicC₁₋₆alkyl; R_(9a) is hydrogen and R_(10a) is hydrogen or substituted orunsubstituted, linear or breached, cyclic or acyclic C₁₋₆alkyl; and Q isOR^(Q′),wherein R^(Q′) is hydrogen or substituted or unsubstituted,linear or branched, cyclic or acyclic alkyl.
 2. The compound of claim 1wherein R² is substituted or unsubstituted, linear or branched, cyclicor acyclic C₁₋₆ alkyl.
 3. The compound of claim 1 having the followingstereochemistry:


4. The compound of claim 3 wherein R⁵ and R^(9a) are each hydrogen, andR₆, R₇, R_(8a) and R_(10a) are each independently alkyl, whereby thealkyl moiety may be substituted or unsubstituted, linear or branched,cyclic or acyclic.
 5. The compound of claim 3 wherein R₆ is tert-butyl,R₇ and R_(10a) are each methyl and R_(8a) is iso-propyl.
 6. The compoundof claim 1 wherein G, J and M are each CH₂; j, l and m are each 1; andthe moiety —X₁—(CR₃R₄)_(n)NR₁R₂ has the following structure:

wherein R_(L1) and R_(L2) are each independently hydrogen or analiphatic, alicyclic, or aryl moiety.
 7. The compound of claim 6 whereinR₂ is hydrogen or substituted or unsubstituted, linear or branched,cyclic or acyclic C₁₋₆alkyl; R_(L1) and R_(L2) are each independentlyhydrogen, substituted or unsubstituted, linear or branched, cyclic oracyclic C₁₋₆alkyl or substituted or unsubstituted aryl.
 8. The compoundof claim 1 wherein R₂ is methyl, R₅ is hydrogen, R₆ is tert-butyl, R₇ ismethyl, R_(8a) is iso-propyl, and the moiety —X₁—(CR₃R₄)_(n)NR₁R₂ hasthe following structure:

wherein R_(L1) and R_(L2) are each independently hydrogen or substitutedor unsubstituted, linear or branched, cyclic or acyclic C₁₋₆alkyl. 9.The compound of claim 1 having the structure:

or pharmaceutically acceptable salt thereof.
 10. The compound of claim 1having the structure:

wherein Q is OH or OEt; or pharmaceutically acceptable salt thereof. 11.The compound of claim 1 having the structure:

or pharmaceutically acceptable salt thereof.
 12. The compound of claim 1having the structure:

or pharmaceutically acceptable salt thereof.
 13. The compound of claim 1having the structure:

or pharmaceutically acceptable salt thereof.
 14. A pharmaceuticalcomposition comprising a compound of claim 1, and a pharmaceuticallyacceptable carrier or diluent.
 15. The compound of claim 1 whereinR_(8a) is methyl, ethyl, propyl, iso-propyl, or sec-butyl.
 16. Thecompound of claim 1 wherein R₅ is hydrogen.
 17. The compound of claim 1wherein R₆ is tert-butyl or iso-propyl.
 18. The compound of claim 1wherein R₇ is hydrogen, methyl or ethyl.
 19. The compound of claim 1wherein R_(10a) is methyl.
 20. The pharmaceutical composition of claim14 further comprising an additional therapeutic agent.
 21. The compoundof claim 1 wherein R₂ is methyl or iso-propyl, R₅ is hydrogen, R₆ istert-butyl, R₇ is methyl, R_(8a) is iso-propyl, and the moiety—X1—(CR₃R₄)_(n)NR₁R₂ has the following structure:

wherein R^(iv) is hydrogen or substituted or unsubstituted, linear orbranched, cyclic or acyclic C₁₋₆alkyl.